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1.
Am J Nurs ; 121(2): 26-27, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33497124

RESUMO

Baloxavir marboxil (Xofluza), an antiviral flu treatment, has now been approved to prevent influenza.Patients should avoid taking calcium, aluminum, or magnesium products while receiving baloxavir as this will lead to a loss of antiviral efficacy.


Assuntos
Dibenzotiepinas/farmacologia , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Morfolinas/farmacologia , Piridonas/farmacologia , Triazinas/farmacologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Dibenzotiepinas/uso terapêutico , Humanos , Morfolinas/uso terapêutico , Piridonas/uso terapêutico , Triazinas/uso terapêutico
2.
Cancer Sci ; 112(4): 1556-1566, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33506571

RESUMO

MET mutations leading to exon 14 skipping (METΔex14) are strong molecular drivers for non-small-cell lung cancer (NSCLC). Capmatinib is a highly potent, selective oral MET inhibitor that showed clinically meaningful efficacy and a manageable safety profile in a global phase II study (GEOMETRY mono-1, NCT02414139) in patients with advanced METΔex14-mutated/MET-amplified NSCLC. We report results of preplanned analyses of 45 Japanese patients according to MET status (METΔex14-mutated or MET-amplified) and line of therapy (first- [1L] or second-/third-line [2/3L]). The starting dose was 400 mg twice daily. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent review committee. A key secondary endpoint was duration of response (DOR). Among METΔex14-mutated patients, in the 1L group, one patient achieved partial response (DOR of 4.24 months) and the other had stable disease. In the 2/3L group, the ORR was 36.4% (95% confidence interval [CI] 10.9%-69.2%), median DOR was not evaluable, and progression-free survival was 4.70 months. One patient (2/3L group) showed partial resolution of brain lesions per independent neuroradiologist review. In MET-amplified patients with a MET gene copy number of ≥10, the ORR was 100% (2/2 patients) in the 1L group and 45.5% (5/11 patients) in the 2/3L group, with DOR of 8.2 and 8.3 months, respectively. Common treatment-related adverse events among the 45 Japanese patients were blood creatinine increased (53.3%), nausea (35.6%), and oedema peripheral (31.1%); most were grade 1/2 severity. In conclusion, capmatinib was effective and well tolerated by Japanese patients with METΔex14/MET-amplified NSCLC, consistent with the overall population.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Éxons/genética , Imidazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Triazinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão , Masculino , Mutação
3.
Drugs Today (Barc) ; 56(9): 561-571, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33025950

RESUMO

Avapritinib is a tyrosine kinase inhibitor (TKI) that has recently received Food and Drug Administration (FDA) approval for the treatment of metastatic or unresectable gastrointestinal stromal tumors harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation. Mutations in the activation loop of PDGFRA or KIT confer resistance to conventional TKIs due to structural changes in the receptor. Avapritinib was developed to selectively target these mutations, thereby offering a new treatment option for patients in whom imatinib, sunitinib, and regorafenib have failed. This review covers the basic science and preclinical studies that guided avapritinib's development, in addition to the data currently available from early clinical studies as well as those later-stage trials that led to its approval.


Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Triazinas/uso terapêutico , Ensaios Clínicos como Assunto , Tumores do Estroma Gastrointestinal/genética , Humanos , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Estados Unidos
4.
Zhonghua Wei Chang Wai Ke Za Zhi ; 23(9): 866-871, 2020 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-32927511

RESUMO

The diagnosis and treatment of gastrointestinal stromal tumor (GIST) is getting more and more standardized. In the last two decades, due to the elucidation of molecular mechanism of tumorigenesis, as well as the effectiveness of tyrosine kinase inhibitors, GIST has become well-known as one of the most classical models of targeted therapy on solid tumors in the precision medicine era. The National Comprehensive Cancer Network (NCCN) issued the latest version of clinical practice guideline on soft tissue sarcoma in February 2020. Compared with previous versions, the new version of the guideline highlighted the treatment recommendations of avapritinib, which further promoted the precise targeted treatment of GIST.


Assuntos
Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/terapia , Guias de Prática Clínica como Assunto/normas , Antineoplásicos/uso terapêutico , Humanos , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Triazinas/uso terapêutico
5.
Zhonghua Wei Chang Wai Ke Za Zhi ; 23(9): 911-916, 2020 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-32927518

RESUMO

Imatinib has created the era of precise treatment of gastrointestinal stromal tumor (GIST). However, in recent years, there has been a lack of satisfactory drugs for imatinib resistance. Recently, the emergence of a series of new agents not only brings new hope to break this situation, but also verifies that the drug development of GIST treatment still needs to lock the driving gene as the main target. New drugs, such as avapritinib and ripretinib, have shown surprising therapeutic efficacy, which may lead to a new situation in the treatment of GIST. The precise treatment of GIST guided by different primary gene mutations and secondary drug resistance mutations will replace the traditional guidelines based on the number of treatment lines.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Antineoplásicos/farmacologia , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêutico , Ureia/análogos & derivados , Ureia/farmacologia , Ureia/uso terapêutico
6.
N Engl J Med ; 383(10): 944-957, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32877583

RESUMO

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. METHODS: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status (MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. RESULTS: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. CONCLUSIONS: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imidazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Triazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Edema/induzido quimicamente , Éxons , Feminino , Dosagem de Genes , Humanos , Imidazóis/efeitos adversos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/genética , Triazinas/efeitos adversos
7.
N Engl J Med ; 383(4): 309-320, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32640124

RESUMO

BACKGROUND: Baloxavir marboxil (baloxavir) is a polymerase acidic protein (PA) endonuclease inhibitor with clinical efficacy in the treatment of uncomplicated influenza, including in outpatients at increased risk for complications. The postexposure prophylactic efficacy of baloxavir in the household setting is unclear. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the postexposure prophylactic efficacy of baloxavir in household contacts of index patients with confirmed influenza during the 2018-2019 season in Japan. The participants were assigned in a 1:1 ratio to receive either a single dose of baloxavir or placebo. The primary end point was clinical influenza, as confirmed by reverse-transcriptase-polymerase-chain-reaction testing, over a period of 10 days. The occurrence of baloxavir-selected PA substitutions associated with reduced susceptibility was assessed. RESULTS: A total of 752 household contacts of 545 index patients were randomly assigned to receive baloxavir or placebo. Among the index patients, 95.6% had influenza A virus infection, 73.6% were younger than 12 years of age, and 52.7% received baloxavir. Among the participants who could be evaluated (374 in the baloxavir group and 375 in the placebo group), the percentage in whom clinical influenza developed was significantly lower in the baloxavir group than in the placebo group (1.9% vs. 13.6%) (adjusted risk ratio, 0.14; 95% confidence interval [CI], 0.06 to 0.30; P<0.001). Baloxavir was effective in high-risk, pediatric, and unvaccinated subgroups of participants. The risk of influenza infection, regardless of symptoms, was lower with baloxavir than with placebo (adjusted risk ratio, 0.43; 95% CI, 0.32 to 0.58). The incidence of adverse events was similar in the two groups (22.2% in the baloxavir group and 20.5% in the placebo group). In the baloxavir group, the viral PA substitutions I38T/M or E23K were detected in 10 (2.7%) and 5 (1.3%) participants, respectively. No transmission of these variants from baloxavir-treated index patients to participants in the placebo group was detected; however, several instances of transmission to participants in the baloxavir group could not be ruled out. CONCLUSIONS: Single-dose baloxavir showed significant postexposure prophylactic efficacy in preventing influenza in household contacts of patients with influenza. (Funded by Shionogi; Japan Primary Registries Network number, JapicCTI-184180.).


Assuntos
Antivirais/uso terapêutico , Transmissão de Doença Infecciosa/prevenção & controle , Vírus da Influenza A , Influenza Humana/prevenção & controle , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Criança , Pré-Escolar , Dibenzotiepinas , Método Duplo-Cego , Endonucleases/antagonistas & inibidores , Família , Feminino , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/isolamento & purificação , Influenza Humana/transmissão , Influenza Humana/virologia , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Morfolinas , Oxazinas/administração & dosagem , Oxazinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridonas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tiepinas/administração & dosagem , Tiepinas/efeitos adversos , Triazinas/administração & dosagem , Triazinas/efeitos adversos
8.
BMC Infect Dis ; 20(1): 478, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32631240

RESUMO

BACKGROUND: Extended use of oseltamivir in an immunocompromised host could reportedly induce neuraminidase gene mutation possibly leading to oseltamivir-resistant influenza A/H3N2 virus. To our knowledge, no report is available on the clinical course of a severely immunocompromised patient with a dual E119D/R292K neuraminidase mutated-influenza A/H3N2 during the administration of peramivir. CASE PRESENTATION: A 49-year-old male patient was admitted for second allogeneic hematopoietic cell transplantation for active acute leukemia. The patient received 5 mg prednisolone and 75 mg cyclosporine and had severe lymphopenia (70/µL). At the time of hospitalization, the patient was diagnosed with upper tract influenza A virus infection, and oseltamivir treatment was initiated immediately. However, the patient was intolerant to oseltamivir. The following day, treatment was changed to peramivir. Despite a total period of neuraminidase-inhibitor administration of 16 days, the symptoms and viral shedding continued. Changing to baloxavir marboxil resolved the symptoms, and the influenza diagnostic test became negative. Subsequently, sequence analysis of the nasopharyngeal specimen revealed the dual E119D/R292K neuraminidase mutant influenza A/H3N2. CONCLUSIONS: In a highly immunocompromised host, clinicians should take care when peramivir is used for extended periods to treat influenza virus A/H3N2 infection as this could potentially leading to a dual E119D/R292K substitution in neuraminidase protein. Baloxavir marboxil may be one of the agents that can be used to treat this type of mutated influenza virus infection.


Assuntos
Antivirais/uso terapêutico , Ciclopentanos/uso terapêutico , Farmacorresistência Viral/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Guanidinas/uso terapêutico , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/tratamento farmacológico , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Ácidos Carbocíclicos , Ciclopentanos/efeitos adversos , Ciclopentanos/farmacologia , Dibenzotiepinas , Farmacorresistência Viral/genética , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Guanidinas/efeitos adversos , Guanidinas/farmacologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Hospedeiro Imunocomprometido , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Morfolinas , Mutação , Neuraminidase/antagonistas & inibidores , Neuraminidase/genética , Oseltamivir/uso terapêutico , Piridonas , Transplante Homólogo/métodos , Resultado do Tratamento , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/genética
9.
Respir Investig ; 58(5): 403-408, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32605828

RESUMO

BACKGROUND: Nosocomial (hospital-acquired) influenza A virus infection is a very important clinical issue. The objective of this study is to describe the effect of baloxavir marboxil in controlling an outbreak of this infection. METHODS: A retrospective observational study was performed to assess the effectiveness of baloxavir marboxil in the treatment of nosocomial infections caused by oseltamivir-resistant influenza virus A. RESULTS: In September 2019, there was an outbreak of nosocomial influenza A(H1N1)pdm09 viral infection in one out of three facility wards for inpatients at the Okinawa Nanbu Regional Center for Children with Special Needs. Symptomatic staff members were kept off duty until they remained afebrile for 2 days. Prophylactic oseltamivir was administered to inpatients (n = 37) and to staff members (n = 16) who voluntarily requested the drug. However, both inpatients and staff members showed influenza A infection during prophylactic use of oseltamivir. The A(H1N1)pdm09 virus sample obtained from one patient was shown to be oseltamivir-resistant. After administration of baloxavir marboxil, the nosocomial outbreak gradually ceased. Moreover, the time (hours) to alleviation of fever in the oseltamivir group (n = 11) and baloxavir marboxil group (n = 13) was significantly different (p = 0.0034). CONCLUSION: Our report provides evidence for the usefulness of baloxavir marboxil in treating influenza A patients who have received prophylactic doses of oseltamivir. This is the first report describing the successful use of baloxavir marboxil for of a nosocomial outbreak caused by oseltamivir-resistant influenza A virus.


Assuntos
Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/virologia , Farmacorresistência Viral , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Oseltamivir , Oxazinas/uso terapêutico , Profilaxia Pré-Exposição , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/prevenção & controle , Dibenzotiepinas , Surtos de Doenças , Feminino , Humanos , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Japão/epidemiologia , Masculino , Morfolinas , Piridonas , Estudos Retrospectivos , Resultado do Tratamento
10.
Lancet Oncol ; 21(7): 935-946, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32615108

RESUMO

BACKGROUND: Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR). METHODS: NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov, NCT02508532. FINDINGS: Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19·1 months [IQR 9·2-25·5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15·9 months [IQR 9·2-24·9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the dose-escalation and dose-expansion parts, all doses), treatment-related grade 3-4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76-95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30-400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2). INTERPRETATION: Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. FUNDING: Blueprint Medicines.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mutação , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Triazinas/uso terapêutico , Idoso , Feminino , Seguimentos , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
11.
Nat Commun ; 11(1): 2750, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32487990

RESUMO

Influenza viruses annually kill 290,000-650,000 people worldwide. Antivirals can reduce death tolls. Baloxavir, the recently approved influenza antiviral, inhibits initiation of viral mRNA synthesis, whereas oseltamivir, an older drug, inhibits release of virus progeny. Baloxavir blocks virus replication more rapidly and completely than oseltamivir, reducing the duration of infectiousness. Hence, early baloxavir treatment may indirectly prevent transmission. Here, we estimate impacts of ramping up and accelerating baloxavir treatment on population-level incidence using a new model that links viral load dynamics from clinical trial data to between-host transmission. We estimate that ~22 million infections and >6,000 deaths would have been averted in the 2017-2018 epidemic season by administering baloxavir to 30% of infected cases within 48 h after symptom onset. Treatment within 24 h would almost double the impact. Consequently, scaling up early baloxavir treatment would substantially reduce influenza morbidity and mortality every year. The development of antivirals against the SARS-CoV2 virus that function like baloxavir might similarly curtail transmission and save lives.


Assuntos
Antivirais/uso terapêutico , Epidemias , Influenza Humana/tratamento farmacológico , Orthomyxoviridae/efeitos dos fármacos , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Proliferação de Células , Infecções por Coronavirus/tratamento farmacológico , Dibenzotiepinas , Humanos , Influenza Humana/virologia , Morfolinas , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Oxazinas/farmacologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Saúde Pública , Piridinas/farmacologia , Piridonas , RNA Mensageiro/metabolismo , Estações do Ano , Tiepinas/farmacologia , Triazinas/farmacologia , Carga Viral , Replicação Viral/efeitos dos fármacos
12.
Intern Med ; 59(12): 1509-1513, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32536677

RESUMO

Objective Baloxavir marboxil is a novel anti-influenza drug reported to have an early antiviral effect, although it also causes the appearance of variant viruses with a reduced susceptibility to baloxavir. In Japan, four neuraminidase inhibitors (NAIs) have been commonly used to treat patients with influenza. In clinical practice, the differences in the effects of baloxavir and NAIs have not been sufficiently examined. Our objective was to clarify the clinical differences in efficacy between baloxavir and NAIs. Methods A multicenter, observational study was conducted using postcard questionnaires during the 2018-19 influenza season. Patients who were prescribed anti-influenza drugs were provided postcard questionnaires asking about their background characteristics and their body temperatures. The factors associated with the early alleviation of the fever were analyzed, and the duration of the fever was compared between the baloxavir group and the NAI group. Results A total of 295 patients with influenza A, ranging in age from 0-91 years old, were enrolled in this study. A multivariate analysis showed that treatment with baloxavir and a duration from the onset to the start of treatment ≥2.5 days were factors contributing to the early alleviation of the fever from the start of treatment. The duration of the fever was significantly shorter in the baloxavir group than in the NAI group (p=0.002). Conclusion The present survey showed that baloxavir was significantly more effective than NAIs for treating patients with influenza A in clinical practice.


Assuntos
Antivirais/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Influenza Humana/tratamento farmacológico , Neuraminidase/antagonistas & inibidores , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Dibenzotiepinas , Feminino , Humanos , Lactente , Recém-Nascido , Japão , Masculino , Pessoa de Meia-Idade , Morfolinas , Análise Multivariada , Piridonas , Resultado do Tratamento , Adulto Jovem
13.
Lancet Infect Dis ; 20(10): 1204-1214, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32526195

RESUMO

BACKGROUND: Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications. METHODS: We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (<80 kg vs ≥80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011. FINDINGS: 2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73·2 h [95% CI 67·2 to 85·1]) than in the placebo group (102·3 h [92·7 to 113·1]; difference 29·1 h [95% CI 14·6 to 42·8]; p<0·0001). The median TTIIS in the oseltamivir group was 81·0 h (95% CI 69·4 to 91·5), with a difference from the baloxavir group of 7·7 h (-7·9 to 22·7). Adverse events were reported in 183 (25%) of 730 patients in the baloxavir group, 216 (30%) of 727 in the placebo group, and 202 (28%) of 721 in the oseltamivir group. Serious adverse events were noted in five patients in the baloxavir group, nine patients in the placebo group, and eight patients in the oseltamivir group; one case each of hypertension and nausea in the placebo group and two cases of transaminase elevation in the oseltamivir group were considered to be treatment related. Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus. INTERPRETATION: Single-dose baloxavir has superior efficacy to placebo and similar efficacy to oseltamivir for ameliorating influenza symptoms in high-risk outpatients. The safety of baloxavir was comparable to placebo. This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications. FUNDING: Shionogi.


Assuntos
Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Oseltamivir/uso terapêutico , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Criança , Dibenzotiepinas , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas , Oxazinas/administração & dosagem , Piridinas/administração & dosagem , Piridonas , Tiepinas/administração & dosagem , Triazinas/administração & dosagem , Adulto Jovem
14.
Parasitol Res ; 119(6): 1955-1968, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32399722

RESUMO

Coccidiosis is a crucial parasitic disease of the poultry industry. As a result of the enormous global economic losses and the increased resistance to the conventional anticoccidial agents, there is a continuous need to find new anticoccidials. Here, the anticoccidial effect of the fluoroquinolone lomefloxacin versus diclazuril in experimentally infected broilers was tested for the treatment of Eimeria tenella infection. Ninety 14-day-old Cobb strain broiler chickens were allocated into five groups, each with 18 chicks. Group 1 (G1) was separated as an uninfected negative control and received no treatment; group 2 (G2), infected untreated (positive control); group 3 (G3), infected and treated with lomefloxacin at a dose rate of 100 ppm in drinking water; group 4 (G4), infected and treated with diclazuril at a dose rate of 2.5 ppm in drinking water; group 5 (G5), infected and treated with lomefloxacin at a dose rate of 100 ppm plus diclazuril at dose rate of 2.5 ppm in drinking water. Clinical signs, mortality rates, number of oocysts per gram of faeces (OPG), growth performance parameters (weight gain: WG and feed conversion ratio: FCR), lesion scoring, haematological and serum biochemical analyses, antioxidant biomarkers and histopathologic inspection of the caeca were used as evaluation criteria for the anticoccidial efficacy of both lomefloxacin and diclazuril. The findings herein showed that administration of lomefloxacin and/or diclazuril improved growth performance parameters (WG, FCR) and significantly (P ≤ 0.05) reduced OPG, and diminished the severity of bloody diarrhoea and mortalities. Additionally, haematological indices and serum biochemical parameters such as ALT, AST, ALP, creatinine, uric acid, total proteins, albumin and globulin were improved. Finally, a significant elevation in the levels of the antioxidant biomarkers was observed in the chicks of G3, G4 and G5 as compared with those of G2.


Assuntos
Galinhas/parasitologia , Coccidiose/veterinária , Coccidiostáticos/farmacologia , Eimeria tenella , Fluoroquinolonas/uso terapêutico , Doenças das Aves Domésticas/tratamento farmacológico , Animais , Ceco/patologia , Coccidiose/tratamento farmacológico , Fezes/parasitologia , Nitrilos/uso terapêutico , Oocistos/efeitos dos fármacos , Doenças das Aves Domésticas/parasitologia , Triazinas/uso terapêutico , Ganho de Peso/efeitos dos fármacos
16.
Lancet Haematol ; 7(4): e309-e319, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32145771

RESUMO

BACKGROUND: Mutations in isocitrate dehydrogenase-2 (IDH2) occur in around 5% of patients with myelodysplastic syndromes. Neomorphic activity of mutant IDH2 proteins results in hypermethylation of DNA and histones, leading to blocked haemopoietic differentiation. Enasidenib, an inhibitor of mutated IDH2 proteins, induces responses in patients with IDH2-mutated, relapsed or refractory acute myeloid leukaemia. We aimed to establish the clinical outcomes of enasidenib monotherapy in a subgroup of patients with myelodysplastic syndromes harbouring mutations in IDH2 from the AG221-C-001 trial. METHODS: The multicentre, open-label, phase 1-2 AG221-C-001 trial enrolled patients with advanced haematological malignancies (2008 WHO criteria) harbouring an IDH2 mutation. The present study is a subgroup analysis of patients with IDH2-mutated myelodysplastic syndromes in the phase 1 dose-escalation and expansion portions of the trial. Patients with myelodysplastic syndromes were aged 18 years or older with an ECOG performance status score of 2 or lower, and were relapsed or refractory to, or ineligible for, standard treatments. Patients received oral doses of enasidenib at 60-300 mg per day in repeated 28-day treatment cycles. In this subgroup analysis, we focused on the safety and activity of enasidenib as main outcomes. Overall response rate, duration of response, and overall and event-free survival analyses were by intention-to-treat. Safety was assessed in all participants who received at least one dose of study drug in terms of treatment-emergent adverse events. The AG221-C-001 trial is registered on ClinicalTrials.gov, NCT01915498, status ongoing but closed to recruitment. FINDINGS: 17 patients with myelodysplastic syndromes harbouring an IDH2 mutation (median age, 67·0 years [IQR 60·5-73·0]) were enrolled between Feb 18, 2014, and Sept 1, 2015. At data cutoff (Oct 1, 2018), after a median follow-up of 11·0 months (IQR 6·8-23·0), all patients had discontinued enasidenib, with a median of 3 treatment cycles (2-15) for all patients (five [29%] received ≥12 cycles). At entry, three (18%) patients had relapsed after allogeneic stem-cell transplants, 13 (76%) had previously received therapy with hypomethylating agents, and ten (59%) had received at least two previous therapies. No dose-limiting toxicities were reported. The most common treatment-emergent adverse events were diarrhoea and nausea (in nine [53%] patients each). Most common grade 3-4 treatment-emergent adverse events were indirect hyperbilirubinaemia (in six [35%] patients), pneumonia (in five [29%] patients), and thrombocytopaenia (in four [24%] patients). Serious treatment-emergent adverse events in more than one patient were pneumonia (in five [29% patients); tumor lysis syndrome (in three [18%] patients); and sepsis, atrial flutter, indirect hyperbilirubinaemia, cerebral hemorrhage, and mental status change (in two [12%] patients each). No treatment-related deaths occurred. An overall response was achieved in 9 patients (53% [95% CI 28-77]), with a median duration of response of 9·2 months (95% CI 1·0-not reached). Six (46%) of 13 patients previously treated with hypomethylating agents responded. Median overall survival was 16·9 months (95% CI 1·5-32·3), and median event-free survival was 11·0 months (1·5-16·7). INTERPRETATION: Enasidenib is generally well tolerated and can induce responses in patients with mutant IDH2 myelodysplastic syndromes, including in those who have had previous therapy with hypomethylating agents. Testing for IDH2 mutations in myelodysplastic syndromes is essential for identifying patients who might benefit from enasidenib therapy, including those patients in whom conventional treatments have been unsuccessful. FUNDING: Celgene and Agios Pharmaceuticals.


Assuntos
Aminopiridinas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Triazinas/uso terapêutico , Idoso , Aminopiridinas/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Hiperbilirrubinemia/etiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Polimorfismo de Nucleotídeo Único , Taxa de Sobrevida , Resultado do Tratamento , Triazinas/efeitos adversos
18.
Transl Res ; 220: 33-42, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32088166

RESUMO

Influenza viruses are a major threat to human health globally. In addition to further improving vaccine prophylaxis, disease management through antiviral therapeutics constitutes an important component of the current intervention strategy to prevent advance to complicated disease and reduce case-fatality rates. Standard-of-care is treatment with neuraminidase inhibitors that prevent viral dissemination. In 2018, the first mechanistically new influenza drug class for the treatment of uncomplicated seasonal influenza in 2 decades was approved for human use. Targeting the PA endonuclease subunit of the viral polymerase complex, this class suppresses viral replication. However, the genetic barrier against viral resistance to both drug classes is low, pre-existing resistance is observed in circulating strains, and resistant viruses are pathogenic and transmit efficiently. Addressing the resistance problem has emerged as an important objective for the development of next-generation influenza virus therapeutics. This review will discuss the status of influenza therapeutics including the endonuclease inhibitor baloxavir marboxil after its first year of clinical use and evaluate a subset of direct-acting antiviral candidates in different stages of preclinical and clinical development.


Assuntos
Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Amidas/uso terapêutico , Anticorpos Neutralizantes/sangue , Citidina/análogos & derivados , Dibenzotiepinas , Farmacorresistência Viral , Humanos , Hidroxilaminas , Morfolinas , Neuraminidase/antagonistas & inibidores , Oxazinas/uso terapêutico , Pirazinas/uso terapêutico , Piridinas/uso terapêutico , Piridonas , Ribonucleosídeos/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Replicação Viral/efeitos dos fármacos
19.
Blood ; 135(16): 1365-1376, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32106312

RESUMO

Systemic mastocytosis (SM) has greatly benefited from the broad application of precision medicine techniques to hematolymphoid neoplasms. Sensitive detection of the recurrent KIT D816V mutation and use of next-generation sequencing (NGS) panels to profile the genetic landscape of SM variants have been critical adjuncts to the diagnosis and subclassification of SM, and development of clinical-molecular prognostic scoring systems. Multilineage KIT involvement and multimutated clones are characteristic of advanced SM (advSM), especially SM with an associated hematologic neoplasm (AHN). A major challenge is how to integrate conventional markers of mast cell disease burden (percentage of bone marrow mast cell infiltration and serum tryptase levels) with molecular data (serial monitoring of both KIT D816V variant allele frequency and NGS panels) to lend more diagnostic and prognostic clarity to the heterogeneous clinical presentations and natural histories of advSM. The approval of the multikinase/KIT inhibitor midostaurin has validated the paradigm of KIT inhibition in advSM, and the efficacy and safety of second-generation agents, such as the switch-control inhibitor ripretinib (DCC-2618) and the D816V-selective inhibitor avapritinib (BLU-285) are being further defined in ongoing clinical trials. Looking forward, perhaps the most fruitful marriage of the advances in molecular genetics and treatment will be the design of adaptive basket trials that combine histopathology and genetic profiling to individualize treatment approaches for patients with diverse AHNs and relapsed/refractory SM.


Assuntos
Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/terapia , Animais , Aberrações Cromossômicas , Transplante de Células-Tronco Hematopoéticas , Humanos , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Mutação , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/genética , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Estaurosporina/análogos & derivados , Estaurosporina/uso terapêutico , Triazinas/uso terapêutico
20.
Expert Opin Pharmacother ; 21(8): 871-882, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32108532

RESUMO

INTRODUCTION: With the rising prevalence of type 2 diabetes (T2D), there is a substantial interest in novel, glucose-lowering drugs that may complement existing treatment options. Imeglimin is an oral antidiabetic agent currently in clinical development. AREAS COVERED: This review is based on a literature search using PubMed and Embase including all published manuscripts and presentations concerning imeglimin. Supplementary information was retrieved from the manufacturer's official webpage. Preclinical and clinical data are summarized with a focus on mechanisms of action as well as clinical efficacy and safety in T2D. EXPERT OPINION: Imeglimin's mode of action seems to be improved mitochondrial function in pancreatic beta cells leading to improved insulin secretion and lowering of plasma glucose levels. In clinical trials of up to 24 weeks, imeglimin in doses of 1,000-1,500 mg twice daily conferred modest reductions in glycates hemoglobin A1c of 6-11 mmol/mol (0.5-1.0%) (placebo-adjusted) as a monotherapy and 7 mmol/mol (0.6%) as an add-on therapy to metformin or sitagliptin in patients with T2D. Reported adverse effects were mainly gastrointestinal discomfort. The position of imeglimin among other pharmacotherapies in the treatment of T2D will be determined based on future studies more clearly outlining the safety and long-term cardiovascular effects. ABBREVIATIONS: AUC: area under the curve; BID: twice daily; DPP-4: dipeptidyl peptidase 4; GLP-1R: glucagon-like peptide-1 receptor; HbA1c: glycated hemoglobin A1c; HFHSD: high-fat high-sucrose diet; OAD: oral antidiabetic; OD: once daily; OGTT: oral glucose tolerance test; PPAR-γ: peroxisome proliferator-activated receptor gamma; PTP: permeability transition pore; SGLT-2: sodium-glucose transport protein 2; STZ: streptozotocin; T2D: type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Triazinas/uso terapêutico , Administração Oral , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Quimioterapia Combinada , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Triazinas/administração & dosagem
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