RESUMO
Tecovirimat is the first-line antiviral treatment recommended for severe mpox or for persons with mpox who are at risk for severe disease; tecovirimat is available in the United States under an expanded access investigational new drug (IND) protocol. During the 2022-2023 mpox outbreak, local U.S. health jurisdictions facilitated access to tecovirimat. In June 2022, Los Angeles County (LAC) rapidly developed strategies for tecovirimat distribution using existing medical countermeasure distribution networks established by the Public Health Emergency Preparedness Program and the Hospital Preparedness Program, creating a hub and spoke distribution network consisting of 44 hub facilities serving 456 satellite sites across LAC. IND patient intake forms were analyzed to describe mpox patients treated with tecovirimat. Tecovirimat treatment data were matched with case surveillance data to calculate time from specimen collection to patients receiving tecovirimat. Among 2,281 patients with mpox in LAC, 735 (32%) received tecovirimat during June 2022-January 2023. Among treated patients, approximately two thirds (508; 69%) received treatment through community clinics and pharmacies. The median interval from specimen collection to treatment was 2 days (IQR = 0-5 days). Local data collection and analysis helped to minimize gaps in treatment access and facilitated network performance monitoring. During public health emergencies, medical countermeasures can be rapidly deployed across a large jurisdiction using existing distribution networks, including clinics and pharmacies.
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Antivirais , Surtos de Doenças , Mpox , Humanos , Surtos de Doenças/prevenção & controle , Los Angeles/epidemiologia , Pessoa de Meia-Idade , Adulto , Adolescente , Feminino , Masculino , Adulto Jovem , Idoso , Antivirais/uso terapêutico , Criança , Mpox/epidemiologia , Pré-Escolar , Lactente , Pirrolidinas , Benzamidas/uso terapêutico , Idoso de 80 Anos ou mais , FtalimidasRESUMO
ABSTRACT: Venous thromboembolism (VTE) is a prevalent yet preventable cause of death, particularly among hospitalized patients. Studies have shown that the risk of VTE remains high for up to 6 months after discharge, highlighting the need for extended thromboprophylaxis as a viable treatment approach. Despite the availability of several anticoagulant drugs such as vitamin K antagonists, heparinoids, rivaroxaban, apixaban, edoxaban, and dabigatran, none of them has received approval from the US Food and Drug Administration for long-term thromboprophylaxis. However, an emerging factor Xa inhibitor called betrixaban has shown promising results in Phase II and phase III trials, positioning itself as the first and only US Food and Drug Administration-approved anticoagulant for extended thromboprophylaxis in hospitalized patients after discharge. Betrixaban offers distinct pharmacological characteristics, including a long half-life, low renal excretion, and unique hepatic metabolism, making it an attractive option for various theoretical uses. Numerous articles have been published discussing the safety and efficacy of betrixaban, all of which have emphasized its usefulness and practicality. However, there has been limited discussion regarding its weaknesses and areas of ambiguity. Therefore, this article aimed to explore the challenges faced during the approval process of betrixaban and provide a comprehensive review of the literature on its advantages and disadvantages as a long-term prophylaxis approach for VTE. Furthermore, we aim to identify the ambiguous points that require further investigation in future studies.
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Anticoagulantes , Piridinas , Tromboembolia Venosa , Humanos , Anticoagulantes/efeitos adversos , Tromboembolia Venosa/prevenção & controle , Benzamidas/farmacologia , Rivaroxabana/uso terapêutico , Fibrinolíticos/uso terapêuticoRESUMO
Unemployment is more common among people living with HIV (PLWH) compared to the general population. PLWH who are employed have better physical and mental health outcomes compared to unemployed PLWH. The main objective of this mixed-methods study was to conduct a program evaluation of Employment Action (EACT), a community-based program that assists PLWH in Toronto, Ontario, Canada to maintain meaningful employment. We extracted quantitative data from two HIV services databases used by EACT, and collected qualitative data from 12 individuals who had been placed into paid employment through EACT. From 131 clients included in the analysis, 38.1% (n = 50) maintained their job for at least 6 weeks within the first year of enrollment in the EACT program. Gender, ethnicity, age, and first language did not predict employment maintenance. Our interviews highlighted the barriers and facilitators to effective service delivery. Key recommendations include implementing skills training, embedding PLWH as EACT staff, and following up with clients once they gain employment. Investment in social programs such as EACT are essential for strengthening their data collection capacity, active outreach to service users, and sufficient planning for the evaluation phase prior to program implementation.
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Benzamidas , Infecções por HIV , Tiazóis , Humanos , Infecções por HIV/epidemiologia , Infecções por HIV/psicologia , Emprego , Ontário/epidemiologia , Desemprego , Avaliação de Programas e Projetos de SaúdeRESUMO
Outbreaks of monkeypox in Europe and North America have been reported since May 2022. At the end of July, we encountered the first two cases of monkeypox diagnosed in Japan. Case 1 was a white man who traveled to Spain where he had sexual intercourse with men. He presented to our hospital with fever, rash, and tiredness, and was diagnosed with monkeypox based on positive PCR test results from the skin lesions. He was admitted to our hospital, received tecovirimat 600 mg twice daily, and was discharged on day 15. Case 2 involved a Japanese man who visited us because of fatigue, muscle pain, headache, and oral ulcers. He was living in New York and traveled to Japan one day before presentation. He had experienced sexual intercourse with men four times during the previous month. The patient was diagnosed with monkeypox based on positive PCR results from the blood. He was admitted to our hospital, received tecovirimat 600 mg twice daily, and was discharged on day 14. These were the first two cases of monkeypox diagnosed in Japan. Based on their history and epidemiology, the viruses seem to have been imported from Europe and North America, respectively. After initiation of tecovirimat, both patients showed mild symptoms and immediate disappearance of viral DNA. The second case was notable for being diagnosed without skin rash. Our report suggests that tecovirimat could decrease the viral load rapidly, and that our prompt diagnosis contributed to the prevention of a monkeypox outbreak in Japan.
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Exantema , Mpox , Masculino , Humanos , Japão , Hospitalização , Alta do Paciente , Benzamidas , FadigaRESUMO
Monkeypox, caused by the mpox virus, is an emerging infectious eruptive disease, endemic in some African countries, that spread rapidly worldwide from May to December 2022. This new epidemic differs from the previous African ones by its mode of transmission, essentially through intimate contact and/or sexual intercourse, and by the fact that in more than 90 % of cases it affects men who have sex with men. Severe forms of the disease, responsible for significant mortality, have been described in immunosuppressed patients. A third-generation vaccine is available for high-risk groups and several international randomized controlled studies are evaluating the efficacy of tecovirimat. While it is impossible to know whether we will see a new epidemic wave in 2023, only a collective commitment to information sharing will ensure adequate surveillance and an appropriate and rapid preventive and therapeutic answer.
La variole du singe, due au virus mpox, est une maladie infectieuse éruptive émergente, endémique dans certains pays d'Afrique, qui s'est étendue mondialement de mai à décembre 2022. Cette nouvelle épidémie se distingue des précédentes, africaines, par son mode de transmission, essentiellement des contacts intimes et/ou des rapports sexuels, et par le fait qu'elle touche dans plus de 90 % des cas des hommes ayant des relations sexuelles avec d'autres hommes. Des formes graves, responsables d'une mortalité significative, ont été décrites chez des patients immunodéprimés. Un vaccin de troisième génération est disponible pour les groupes à haut risque et plusieurs études internationales randomisées et contrôlées évaluent l'efficacité du técovirimat. S'il est impossible d'exclure ou d'affirmer une nouvelle explosion épidémique en 2023, seul un engagement collectif en faveur d'un partage d'informations permettra d'assurer une réponse préventive et thérapeutique appropriée et rapide.
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Doenças Transmissíveis Emergentes , Mpox , Minorias Sexuais e de Gênero , Masculino , Humanos , Mpox/epidemiologia , Mpox/prevenção & controle , Homossexualidade Masculina , África , Benzamidas , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/prevenção & controleRESUMO
BACKGROUND: In patients with bone metastatic castration-resistant prostate cancer (bmCRPC) on systemic treatment, it is difficult to differentiate between continuous rise of prostate specific antigen (PSA) representing progression, and PSA-surge, which is followed by clinical response or stable disease. The purpose of this study was to evaluate the prognostic value of dynamic changes of alkaline phosphatase (ALP) and lactic acid dehydrogenase (LDH) levels as a predictor of clinical efficacy or therapeutic resistance of patients who do not show a sufficient initial PSA decline of ≥50% from baseline during early therapy with Enzalutamide. METHODS: Forty-eight men with bmCRPC on Enzalutamide 07/2010-09/2019 with initially rising PSA were analyzed. We monitored PSA, LDH and ALP at week 0, 2, 4, and every 4 weeks thereafter and analyzed the correlation between ALP rising at 12 weeks with or without LDH-normalization and the association with survival. For this we used Kaplan Meier analysis and uni- and multivariate cox-regression models. RESULTS: In Kaplan-Meier analysis, ALP rising at 12 weeks with or without LDH-normalization was associated with significantly worse median progression-free survival (PFS) of 3 months vs. 5 months (Log rank P = 0.02) and 3 months vs. 5 months (P = 0.01), respectively and overall survival (OS) with 8 months vs. 15 months (P = 0.02) and 8 months vs. 17 months (P < 0.01). In univariate analysis of PFS, ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization and application of Enzalutamide after chemotherapy showed a statistically significant association towards shorter PFS (hazard ratio (HR): 0.51, P = 0.04; HR: 0.48, P = 0.03; HR: 0.48, P = 0.03). Worse OS was significantly associated with ALP rising at 12 weeks alone, ALP rising at 12 weeks without LDH-normalization, and application of Enzalutamide after chemotherapy (HR: 0.47, P = 0.02; HR: 0.36, P < 0.01; HR: 0.31, P < 0.01). In multivariate analysis only the application of Enzalutamide after chemotherapy remained an independent prognostic factor for worse OS (HR: 0.36, P = 0.01). CONCLUSIONS: Dynamic changes of ALP (non-rise) and LDH (normalization) under therapy with Enzalutamide may be associated with clinical benefit, better PFS, and OS in patients with bmCRPC who do not show a PSA decline.
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Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Fosfatase Alcalina , Benzamidas , Humanos , L-Lactato Desidrogenase , Ácido Láctico , Masculino , Nitrilas/uso terapêutico , Feniltioidantoína , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do TratamentoRESUMO
AIMS: Safety profiles of abiraterone and enzalutamide rely mainly on Phase III clinical trials. Our objective was to estimate the incidence rate ratio (IRR) for certain adverse events leading in real life to hospitalization (atrial fibrillation, acute heart failure, ischaemic heart disease, acute kidney injury [AKI], ischaemic stroke, torsade de pointe/QT interval prolongation, hepatitis and seizure), comparing abiraterone to enzalutamide. We also set out to discuss previously identified safety signals. METHOD: Using the French National Health Insurance System database, all patients newly exposed to abiraterone or enzalutamide between 2013 and 2017 and followed until 31 December 2018 were targeted. IRRs for each event were estimated using a Poisson model in a sub-population of patients without contraindications or precautions for use for either treatment. RESULTS: Among 11 534 new users of abiraterone and enzalutamide, AKI (IRR 1.42, 95% CI: 1.01-2.00), liver monitoring suggestive of hepatic damage (IRR 3.06, 95% CI: 2.66-3.53) and atrial fibrillation (IRR 1.12, 95% CI: 1.05-1.19) were significantly more often observed with abiraterone than with enzalutamide. CONCLUSION: Our study provides knowledge on abiraterone and enzalutamide real-life safety profiles, especially for events leading to hospitalization. Despite several limitations, including the lack of clinical data, the safety signal for AKI under abiraterone is in line with results of an analysis of the French pharmacovigilance database, which requires further specific investigations. Enlightening the clinicians' therapeutic choices for patients treated for prostate cancer, our study should lead to clinicians being cautious in the use of abiraterone.
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Injúria Renal Aguda , Fibrilação Atrial , Isquemia Encefálica , Neoplasias de Próstata Resistentes à Castração , Acidente Vascular Cerebral , Injúria Renal Aguda/induzido quimicamente , Androstenos/efeitos adversos , Fibrilação Atrial/induzido quimicamente , Benzamidas/efeitos adversos , Isquemia Encefálica/induzido quimicamente , Hospitalização , Humanos , Masculino , Nitrilas/efeitos adversos , Feniltioidantoína/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Acidente Vascular Cerebral/induzido quimicamente , Resultado do TratamentoRESUMO
BACKGROUND: Calcium release-activated calcium (CRAC) channel inhibitors block proinflammatory cytokine release, preserve endothelial integrity and may effectively treat patients with severe COVID-19 pneumonia. METHODS: CARDEA was a phase 2, randomized, double-blind, placebo-controlled trial evaluating the addition of Auxora, a CRAC channel inhibitor, to corticosteroids and standard of care in adults with severe COVID-19 pneumonia. Eligible patients were adults with ≥ 1 symptom consistent with COVID-19 infection, a diagnosis of COVID-19 confirmed by laboratory testing using polymerase chain reaction or other assay, and pneumonia documented by chest imaging. Patients were also required to be receiving oxygen therapy using either a high flow or low flow nasal cannula at the time of enrolment and have at the time of enrollment a baseline imputed PaO2/FiO2 ratio > 75 and ≤ 300. The PaO2/FiO2 was imputed from a SpO2/FiO2 determine by pulse oximetry using a non-linear equation. Patients could not be receiving either non-invasive or invasive mechanical ventilation at the time of enrolment. The primary endpoint was time to recovery through Day 60, with secondary endpoints of all-cause mortality at Day 60 and Day 30. Due to declining rates of COVID-19 hospitalizations and utilization of standard of care medications prohibited by regulatory guidance, the trial was stopped early. RESULTS: The pre-specified efficacy set consisted of the 261 patients with a baseline imputed PaO2/FiO2≤ 200 with 130 and 131 in the Auxora and placebo groups, respectively. Time to recovery was 7 vs. 10 days (P = 0.0979) for patients who received Auxora vs. placebo, respectively. The all-cause mortality rate at Day 60 was 13.8% with Auxora vs. 20.6% with placebo (P = 0.1449); Day 30 all-cause mortality was 7.7% and 17.6%, respectively (P = 0.0165). Similar trends were noted in all randomized patients, patients on high flow nasal cannula at baseline or those with a baseline imputed PaO2/FiO2 ≤ 100. Serious adverse events (SAEs) were less frequent in patients treated with Auxora vs. placebo and occurred in 34 patients (24.1%) receiving Auxora and 49 (35.0%) receiving placebo (P = 0.0616). The most common SAEs were respiratory failure, acute respiratory distress syndrome, and pneumonia. CONCLUSIONS: Auxora was safe and well tolerated with strong signals in both time to recovery and all-cause mortality through Day 60 in patients with severe COVID-19 pneumonia. Further studies of Auxora in patients with severe COVID-19 pneumonia are warranted. Trial registration NCT04345614.
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Benzamidas , Tratamento Farmacológico da COVID-19 , Canais de Cálcio Ativados pela Liberação de Cálcio , Pirazinas , Síndrome do Desconforto Respiratório , Adulto , Benzamidas/uso terapêutico , Canais de Cálcio Ativados pela Liberação de Cálcio/antagonistas & inibidores , Humanos , Pirazinas/uso terapêutico , Respiração Artificial , SARS-CoV-2 , Resultado do TratamentoRESUMO
This study aims to investigate the efficacy, safety, and cost-effecctiveness of Qizhi Weitong Granules in the treatment of functional dyspepsia. Specifically, two commonly used clinical protocols for the treatment of functional dyspepsia were selected: Qizhi Weitong Granules+Mosapride vs Mosapride alone(control). Meta-analysis of previous clinical studies was performed to examine the efficacy and safety, and pharmacoeconomic evaluation was carried out according to the results of the Meta-analysis. The cost-effectiveness analysis was carried out to elucidated the incremental cost-effectiveness ratio(ICER), and the sensitivity was analyzed with tornado dia-gram and Monte Carlo simulation. The willingness-to-pay threshold of patients for functional dyspepsia was investigated and compared with the ICER to evaluate whether Qizhi Weitong Granules was cost-effective. The result showed that the effective rate of Qizhi Weitong Granules combined with Mosapride in the treatment of functional dyspepsia was 95.49%, which was higher than that of Mosapride alone(73.30%)(OR=8.52, 95%CI[4.36, 16.64])(P<0.000 1). The two groups showed no significant difference in safety. The price of Qizhi Weitong Granules+Mosapride was higher than that of Mosapride alone. The ICER was 640.29 CNY, 1 506.67 CNY lower than the willingness-to-pay threshold. The sensitivity analysis showed that the analysis results were relatively stable. Thus, Qizhi Weitong Granules+Mosapride is safe, effective, and economical in the treatment of functional dyspepsia, which should be further promoted in clinical settings.
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Dispepsia , Benzamidas , Análise Custo-Benefício , Dispepsia/tratamento farmacológico , Farmacoeconomia , Fármacos Gastrointestinais/uso terapêutico , Humanos , Morfolinas , Resultado do TratamentoRESUMO
BACKGROUND: There are little and inconsistent data from clinical practice on time on treatment with the androgen receptor-targeted drugs (ART) abiraterone and enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC). We assessed time on treatment with ART and investigated predictors of time on treatment. MATERIAL AND METHODS: Time on treatment with ART in men with mCRPC in the patient-overview prostate cancer (PPC), a subregister of the National Prostate Cancer Register (NPCR) of Sweden, was assessed by use of Kaplan-Meier plots and Cox regression. To assess the representativity of PPC for time on treatment, a comparison was made with all men in NPCR who had a filling for ART in the Prescribed Drug Registry. RESULTS: 2038 men in PPC received ART between 2015 and 2019. Median time on treatment in chemo-naïve men was 10.8 (95% confidence interval 9.1-13.1) months for abiraterone and 14.1 (13.5-15.5) for enzalutamide. After the use of docetaxel, time on treatment was 8.2 (6.5-12.4) months for abiraterone and 11.1 (9.8-12.6) for enzalutamide. Predictors of a long time on treatment with ART were long duration of ADT prior to ART, low serum levels of PSA at start of ART, absence of visceral metastasis, good performance status, and no prior use of docetaxel. PPC captured 2522/6337 (40%) of all men in NPCR who had filled a prescription for ART. Based on fillings in the Prescribed Drug Registry, men in PPC had a slightly longer median time on treatment with ART compared to all men in NPCR, 9.6 (9.1-10.3) vs. 8.6 (6.3-9.1) months. CONCLUSIONS: Time on treatment in clinical practice was similar or shorter than that in published RCTs, due to older age, poorer performance status and more comorbidities.
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Neoplasias de Próstata Resistentes à Castração , Idoso , Androstenos , Benzamidas , Humanos , Masculino , Nitrilas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Suécia/epidemiologia , Resultado do TratamentoRESUMO
SOURCE CITATION: Lebwohl MG, Papp KA, Stein Gold L, et al. Trial of roflumilast cream for chronic plaque psoriasis. N Engl J Med. 2020;383:229-39. 32668113.
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Aminopiridinas , Psoríase , Aminopiridinas/efeitos adversos , Benzamidas/efeitos adversos , Ciclopropanos , Humanos , Psoríase/tratamento farmacológico , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the efficacy and safety of enzalutamide plus androgen deprivation therapy in Japanese men with metastatic hormone-sensitive prostate cancer. METHODS: A post-hoc analysis of the Japanese subgroup in the phase III, randomized, multinational ARCHES study (NCT02677896) was carried out. Patients with metastatic hormone-sensitive prostate cancer were randomized to receive enzalutamide or a placebo, plus androgen deprivation therapy, stratified by disease volume and prior docetaxel therapy. The primary end-point was radiographic progression-free survival. Secondary end-points included time to prostate-specific antigen progression and overall survival. RESULTS: Of 1150 patients, 92 Japanese patients were randomized to enzalutamide (n = 36) or a placebo (n = 56), plus androgen deprivation therapy; none received prior docetaxel. Enzalutamide plus androgen deprivation therapy reduced the risk of radiographic progression or death in Japanese patients by 61% versus the placebo, similar to the overall population. Similar results were observed with secondary end-points, showing clinical benefit of enzalutamide plus androgen deprivation therapy in Japanese patients. Overall survival data were immature. Grade 3-4 adverse events were reported in 47% and 25% of the enzalutamide and placebo groups, respectively. Nasopharyngitis, hypertension and abnormal hepatic function were reported more frequently in Japanese patients versus the overall population. CONCLUSIONS: Enzalutamide plus androgen deprivation therapy has clinical benefit with a tolerable safety profile in Japanese men with metastatic hormone-sensitive prostate cancer, consistent with the overall population.
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Antagonistas de Androgênios , Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/efeitos adversos , Androgênios , Benzamidas , Humanos , Japão , Masculino , Nitrilas , Feniltioidantoína , Resultado do TratamentoRESUMO
In peanut (Arachis hypogaea) production, in-furrow applications of the premix combination of the succinate-dehydrogenase-inhibitor (SDHI) fungicide and nematicide fluopyram and the insecticide imidacloprid are used primarily for management of nematode pests and for preventing feeding damage on foliage caused by tobacco thrips (Frankliniella fusca). Fluopyram is also active against many fungal pathogens. However, the effect of in-furrow applications of fluopyram on early leaf spot (Passalora arachidicola) or late leaf spot (Nothopassalora personata) has not been characterized. The purpose of this study was to determine the effects of in-furrow applications of fluopyram + imidacloprid or fluopyram alone on leaf spot epidemics. Field experiments were conducted in Tifton, GA in 2015, 2016, and 2018 to 2020. In all experiments, in-furrow applications of fluopyram + imidacloprid provided extended suppression of early leaf spot and late leaf spot epidemics compared with the nontreated control. In 2020, there was no difference between the effects of fluopyram + imidacloprid and fluopyram alone on leaf spot epidemics. Results indicated that fluopyram could complement early-season leaf spot management programs. Use of in-furrow applications of fluopyram should be considered as an SDHI fungicide application for resistance management purposes.
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Arachis , Fungicidas Industriais , Benzamidas , Fungicidas Industriais/farmacologia , Doenças das Plantas/prevenção & controle , Piridinas/farmacologiaRESUMO
Soybean (Glycine max) sudden death syndrome (SDS), caused by Fusarium virguliforme, is a key limitation in reaching soybean yield potential, stemming from incomplete disease management through cultural practices and partial host resistance. A fungicidal seed treatment was released in 2014 with the active ingredient fluopyram and was the first chemical management strategy to reduce soybean yield loss stemming from SDS. Although farm level studies have found fluopyram profitable, we were curious to discover whether fluopyram would be beneficial nationally if targeted to soybean fields at risk for SDS yield loss. To estimate economic benefits of fluopyram adoption in SDS at-risk acres, in the light of U.S. public research and outreach from a privately developed product, we applied an economic surplus approach, calculating ex ante net benefits from 2018 to 2032. Through this framework of logistic adoption of fluopyram for alleviation of SDS-associated yield losses, we projected a net benefit of $5.8 billion over 15 years, considering the costs of public seed treatment research and future extension communication. Although the sensitivity analysis indicates that overall net benefits from fluopyram adoption on SDS at-risk acres are highly dependent upon the market price of soybean, the incidence of SDS, the adoption path, and ceiling of this seed treatment, the net benefits still exceeded $407 million in the worst-case scenario.
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Fusarium , Glycine max , Benzamidas , Morte Súbita , Humanos , Doenças das Plantas/prevenção & controle , Piridinas , SementesRESUMO
In the phase 3 study RERISE, patients with newly diagnosed chronic myeloid leukaemia in chronic phase demonstrated significantly faster and higher rates of major molecular response (MMR) with twice-daily radotinib 300 mg (n = 79) or 400 mg (n = 81) than with once-daily imatinib 400 mg (n = 81) after 12 months. With ≥48 months' follow-up, MMR was higher with radotinib 300 mg (86%) or 400 mg (83%) than with imatinib (75%). Among patients with BCR-ABL1 ≤ 10% at three months, MMR and molecular response 4·5 (MR4·5 ) were achieved within 48 months by more radotinib-treated patients (300 mg: 84% and 52%, respectively; 400 mg: 74% and 44%, respectively) than imatinib-treated patients (71% and 44%, respectively). Estimated overall and progression-free survival rates at 48 months were not significantly different between imatinib (94% and 94%, respectively) and radotinib 300 mg (99% and 97%, respectively) or 400 mg (95% and 93%, respectively). The treatment failure rate was significantly higher with imatinib (19%) than with radotinib 300 mg (6%; P = 0·0197) or 400 mg (5%; P = 0·0072). Safety profiles were consistent with previous reports; most adverse events occurred within 12 months. Radotinib continues to demonstrate robust, deep molecular responses, suggesting that treatment-free remission may be attainable.
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Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/complicações , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Pirazinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Feminino , Humanos , Mesilato de Imatinib/farmacologia , Masculino , Pessoa de Meia-Idade , Pirazinas/farmacologia , Resultado do Tratamento , Adulto JovemRESUMO
LESSONS LEARNED: Androgen receptor as assessed by immunohistochemistry is expressed in a high proportion of patients with hepatocellular carcinoma (HCC). Enzalutamide at 160 mg orally daily is safe and tolerable in patients with advanced HCC but has no single-agent antitumor activity. Enzalutamide, a CYP3A4 inducer, at a standard dose of 160 mg reduces the exposure of sorafenib, a CYP3A4 substrate. Enzalutamide and sorafenib is safe and tolerable in patients with advanced HCC, but the addition of enzalutamide to sorafenib did not enhance the antitumor activity of sorafenib. BACKGROUND: Androgen receptor (AR) interference is deleterious to hepatocellular carcinoma (HCC) in preclinical models. METHODS: This is a multicenter, phase Ib study of enzalutamide ± sorafenib in patients with advanced HCC. In part 1, a 3 + 3 dose de-escalation design with expansion established the recommended phase II dose (RP2D) of enzalutamide in patients in whom sorafenib treatment had failed. In part 2, a 3 + 3 dose escalation with expansion established the safety of enzalutamide with sorafenib in treatment-naive patients with HCC. Secondary objectives included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and determination of AR expression by immunohistochemistry. A 7-day run-in with sorafenib alone in part 2 allowed assessment of the impact of enzalutamide on sorafenib pharmacokinetics. RESULTS: In part 1, 16 patients received enzalutamide 160 mg daily. No dose-limiting toxicity (DLT) occurred; 1 patient required dose reduction. Responses were not observed; median PFS and OS were 1.8 (95% confidence interval [CI]: 1.6-3.6) and 7 (95% CI: 3.6 to not reached [NR]) months, respectively. In part 2, patients received sorafenib 400 mg daily (4) or twice a day (8) both with enzalutamide at the recommended phase II dose-no DLTs were observed. ORR was 10% (95% CI: 0.3-44.5), and median PFS and OS were 2.9 (95% CI: 1.6 to NR) and 6.7 (95% CI: 4.6 to NR) months, respectively. Enzalutamide reduced sorafenib exposure by 60%. Tumor AR expression did not associate with outcome. CONCLUSION: Enzalutamide is ineffective in HCC; further development is not supported by this study.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Nitrilas , Feniltioidantoína , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve. METHODS: Subgroups of patients reporting an overall response of "good" or "poor/none" to the most recent use of a triptan at baseline (defined as good or insufficient responders, respectively) and a triptan-naïve subpopulation were derived from combined study participants randomized to receive lasmiditan 50 mg (SPARTAN only), 100 mg or 200 mg, or placebo, as the first dose. Outcomes including headache pain-freedom, most bothersome symptom-freedom, and headache pain relief 2 hours post-first dose of lasmiditan were compared with placebo. Treatment-by-subgroup analyses additionally investigated whether therapeutic benefit varied according to prior triptan response (good or insufficient). RESULTS: Regardless of triptan response, lasmiditan showed higher efficacy than placebo (most comparisons were statistically significant). Treatment-by-subgroup analyses found that the benefit over placebo of lasmiditan did not vary significantly between patients with a good response and those with an insufficient response to triptans. Lasmiditan also showed higher efficacy than placebo in triptan-naïve patients. CONCLUSIONS: Lasmiditan demonstrated comparable efficacy in patients who reported a good or insufficient response to prior triptan use. Lasmiditan also showed efficacy in those who were triptan naïve. Lasmiditan may be a useful therapeutic option for patients with migraine. TRIAL REGISTRATION: SAMURAI (NCT02439320); SPARTAN (NCT02605174).
Assuntos
Benzamidas/administração & dosagem , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Triptaminas/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: Osteoarthritis (OA) is a chronic disease accompanied by severe inflammation. The inflammation activation in the chondrocytes and the degradation of the extracellular matrix were reported to be involved in the progress of OA. Roflumilast is a selective PDE4 inhibitor used for treating chronic obstructive pulmonary disease (COPD) and exerts significant anti-inflammation effects. The present study aims to investigate the effects of Roflumilast on tumor necrosis factor-ß (TNF-ß)-induced inflammation activation and degradation of type 2 collagen in chondrocytes. METHODS: TNF-ß was used to establish the in-vitro inflammation model on ATDC5 chondrocytes. Quantitative real-time polymerase chain reaction (QRT-PCR) and western blot were used to determine the expression level of tumor necrosis factor receptor 2 (TNFR2), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), matrix metalloproteinase 3 (MMP-3), matrix metalloproteinase 13 (MMP-13), type 2 collagen and nuclear factor kappa B (NF-κB) p65. The release of prostaglandin E2 (PGE2), MMP-3, and MMP-13 were evaluated by ELISA. The production of NO was determined by DAF-FM DA staining and the function of the NF-κB promoter was evaluated by Luciferase activity assay. RESULTS: TNFR2 and COX-2 were upregulated and the release of PGE2 was promoted by TNF-ß stimulation, which were all inhibited by Roflumilast. Roflumilast suppressed the promoted iNOS expression and NO production induced by TNF-ß. MMP-3 and MMP-13 were up-regulated, and type 2 collagen was down-regulated by TNF-ß stimulation, which were all reversed by Roflumilast. Roflumilast inhibited the promoted releasing of Interleukin-8 (IL-8) and Interleukin-12 (IL-12), expression of up-regulated NF-κB, and activation of NF-κB transcriptional activity induced by TNF-ß. CONCLUSION: Roflumilast may prevent TNF-ß-induced inflammation activation and degradation of type 2 collagen in chondrocytes.
Assuntos
Aminopiridinas/farmacologia , Benzamidas/farmacologia , Condrócitos/metabolismo , Colágeno Tipo II/metabolismo , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Linfotoxina-alfa , Inibidores da Fosfodiesterase 4/farmacologia , Linhagem Celular , Condrócitos/efeitos dos fármacos , Ciclopropanos/farmacologia , Citocinas/metabolismo , Matriz Extracelular/efeitos dos fármacos , Humanos , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Migraine has been recognized as one of common diseases in the world whose current treatment options are not ideal. Lasmiditan, an oral 5-hydroxytryptamine (HT)1F receptor agonist, appears more promising for the acute treatment of migraine because of considerably better effect profiles with no severe adverse events (AEs). This review aimed to systematically evaluate the efficacy and safety of lasmiditan from the results of randomized controlled trials (RCTs). METHODS: PubMed, Cochrane Library, Embase were searched on lasmiditan for the acute treatment of migraine from inception of the databases to Feb 1, 2020. Pain free and pain relief, global impression (very much/much better), and no/mild disability at 2 h in efficacy; total treatment-emergent adverse events (TEAEs), dizziness, nausea, fatigue, paraesthesia and somnolence in safety were extracted from the included studies. A systematic review and meta-analysis was performed using Review Manager Software version 5.3 (RevMan 5.3). RESULTS: Four RCTs with a total of 4960 subjects met our inclusion criteria. The overall effect estimate showed that lasmiditan was significantly superior to placebo in terms of pain free (RR 1.71, 95% CI 1.55-1.87), pain relief (RR 1.40, 95% CI 1.33-1.47), global impression (very much/much better) (RR 1.55, 95% CI 1.44-1.67), and no/mild disability (RR 1.15, 95% CI 1.10-1.20) at 2 h. For the safety, significant number of patients experienced TEAEs with lasmiditan than with placebo (RR 2.77, 95% CI 2.53-3.03), most TEAEs were central nervous system (CNS)-related and included dizziness (RR 5.81, 95% CI 4.72-7.14), nausea (RR 2.58, 95% CI 1.87-3.57), fatigue (RR 5.38, 95% CI 3.78-7.66), paraesthesia (RR 4.48, 95% CI 3.33-6.02), and somnolence (RR 2.82, 95% CI 2.18-3.66). CONCLUSIONS: This meta-analysis suggests that lasmiditan is effective for the acute treatment of migraine with a higher incidence of CNS-related adverse reactions compared with placebo. Long-term, open-label, multi-dose trials are required to verify the current findings.