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1.
Eur Rev Med Pharmacol Sci ; 24(17): 9169-9171, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32965010

RESUMO

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome has recently become an intriguing target of several chronic and viral diseases. Here, we argue that targeting NLRP3 inflammasome could be a strategy to prevent cardiovascular outcomes [fulminant myocarditis, heart failure, venous thromboembolism (VTE)] and acute respiratory distress syndrome (ARDS) in patients with SARS-CoV-2 infection. We discuss the rationale for NLRP3 targeting in clinical trials as an effective therapeutic strategy aimed to improve prognosis of COVID-19, analyzing the potential of two therapeutic options (tranilast and OLT1177) currently available in clinical practice.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Infecções por Coronavirus/diagnóstico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia Viral/diagnóstico , Betacoronavirus/isolamento & purificação , Ensaios Clínicos como Assunto , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Miocardite/prevenção & controle , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Nitrilos/uso terapêutico , Pandemias , Pneumonia Viral/virologia , Prognóstico , Tromboembolia Venosa/prevenção & controle , ortoaminobenzoatos/uso terapêutico
2.
Nat Commun ; 11(1): 4498, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908142

RESUMO

The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored. Here, we show that AR signalling in the macrophage-like THP-1 cell line supports PCa cell line migration and invasion in culture via increased Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) signalling and expression of its downstream cytokines. Moreover, AR signalling in THP-1 and monocyte-derived macrophages upregulates IL-10 and markers of tissue residency. In conclusion, our data suggest that AR signalling in macrophages may support PCa invasiveness, and blocking this process may constitute one mechanism of anti-androgen therapy.


Assuntos
Macrófagos/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Idoso , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Anilidas/farmacologia , Anilidas/uso terapêutico , Biópsia , Buffy Coat/citologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Quimioterapia Adjuvante , Técnicas de Cocultura , Intervalo Livre de Doença , Humanos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/prevenção & controle , Nitrilos/farmacologia , Nitrilos/uso terapêutico , Intervalo Livre de Progressão , Próstata/patologia , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/terapia , Procedimentos Cirúrgicos Robóticos , Transdução de Sinais/imunologia , Análise de Célula Única , Células THP-1 , Compostos de Tosil/farmacologia , Compostos de Tosil/uso terapêutico
3.
Cochrane Database Syst Rev ; 8: CD009966, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32803882

RESUMO

BACKGROUND: Kidney transplantation is the preferred management for patients with end-stage kidney disease (ESKD). However, it is often complicated by worsening or new-onset diabetes. The safety and efficacy of glucose-lowering agents after kidney transplantation is largely unknown. This is an update of a review first published in 2017. OBJECTIVES: To evaluate the efficacy and safety of glucose-lowering agents for treating pre-existing and new onset diabetes in people who have undergone kidney transplantation. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 16 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs), quasi-RCTs and cross-over studies examining head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in patients who have received a kidney transplant and have diabetes were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Four authors independently assessed study eligibility and quality and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD) or standardised mean difference (SMD). Adverse events were expressed as post-treatment absolute risk differences (RD). Dichotomous clinical outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: Ten studies (21 records, 603 randomised participants) were included - three additional studies (five records) since our last review. Four studies compared more intensive versus less intensive insulin therapy; two studies compared dipeptidyl peptidase-4 (DPP-4) inhibitors to placebo; one study compared DPP-4 inhibitors to insulin glargine; one study compared sodium glucose co-transporter 2 (SGLT2) inhibitors to placebo; and two studies compared glitazones and insulin to insulin therapy alone. The majority of studies had an unclear to a high risk of bias. There were no studies examining the effects of biguanides, glinides, GLP-1 agonists, or sulphonylureas. Compared to less intensive insulin therapy, it is unclear if more intensive insulin therapy has an effect on transplant or graft survival (4 studies, 301 participants: RR 1.12, 95% CI 0.32 to 3.94; I2 = 49%; very low certainty evidence), delayed graft function (2 studies, 153 participants: RR 0.63, 0.42 to 0.93; I2 = 0%; very low certainty evidence), HbA1c (1 study, 16 participants; very low certainty evidence), fasting blood glucose (1 study, 24 participants; very low certainty evidence), kidney function markers (1 study, 26 participants; very low certainty evidence), death (any cause) (3 studies, 208 participants" RR 0.68, 0.29 to 1.58; I2 = 0%; very low certainty evidence), hypoglycaemia (4 studies, 301 participants; very low certainty evidence) and medication discontinuation due to adverse effects (1 study, 60 participants; very low certainty evidence). Compared to placebo, it is unclear whether DPP-4 inhibitors have an effect on hypoglycaemia and medication discontinuation (2 studies, 51 participants; very low certainty evidence). However, DPP-4 inhibitors may reduce HbA1c and fasting blood glucose but not kidney function markers (1 study, 32 participants; low certainty evidence). Compared to insulin glargine, it is unclear if DPP-4 inhibitors have an effect on HbA1c, fasting blood glucose, hypoglycaemia or discontinuation due to adverse events (1 study, 45 participants; very low certainty evidence). Compared to placebo, SGLT2 inhibitors probably do not affect kidney graft survival (1 study, 44 participants; moderate certainty evidence), but may reduce HbA1c without affecting fasting blood glucose and eGFR long-term (1 study, 44 participants, low certainty evidence). SGLT2 inhibitors probably do not increase hypoglycaemia, and probably have little or no effect on medication discontinuation due to adverse events. However, all participants discontinuing SGLT2 inhibitors had urinary tract infections (1 study, 44 participants, moderate certainty evidence). Compared to insulin therapy alone, it is unclear if glitazones added to insulin have an effect on HbA1c or kidney function markers (1 study, 62 participants; very low certainty evidence). However, glitazones may make little or no difference to fasting blood glucose (2 studies, 120 participants; low certainty evidence), and medication discontinuation due to adverse events (1 study, 62 participants; low certainty evidence). No studies of DPP-4 inhibitors, or glitazones reported effects on transplant or graft survival, delayed graft function or death (any cause). AUTHORS' CONCLUSIONS: The efficacy and safety of glucose-lowering agents in the treatment of pre-existing and new-onset diabetes in kidney transplant recipients is questionable. Evidence from existing studies examining the effect of intensive insulin therapy, DPP-4 inhibitors, SGLT inhibitors and glitazones is mostly of low to very low certainty. Appropriately blinded, larger, and higher quality RCTs are needed to evaluate and compare the safety and efficacy of contemporary glucose-lowering agents in the kidney transplant population.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Adamantano/efeitos adversos , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Viés , Causas de Morte , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Jejum/sangue , Hemoglobina A Glicada/metabolismo , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Insulina/uso terapêutico , Insulina Glargina/efeitos adversos , Insulina Glargina/uso terapêutico , Nitrilos/efeitos adversos , Nitrilos/uso terapêutico , Pioglitazona , Complicações Pós-Operatórias/etiologia , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fosfato de Sitagliptina/efeitos adversos , Fosfato de Sitagliptina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Tiazolidinedionas/efeitos adversos , Tiazolidinedionas/uso terapêutico , Transplantados , Vildagliptina
4.
BMC Infect Dis ; 20(1): 527, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698804

RESUMO

BACKGROUND: Conidiobolus spp. (mainly C. coronatus) are the causal agents of rhino-facial conidiobolomycosis, a limited soft tissue infection, which is essentially observed in immunocompetent individuals from tropical areas. Rare cases of invasive conidiobolomycosis due to C. coronatus or other species (C.incongruus, C.lamprauges) have been reported in immunocompromised patients. We report here the first case of invasive pulmonary fungal infection due to Conidiobolus pachyzygosporus in a Swiss patient with onco-haematologic malignancy. CASE PRESENTATION: A 71 year-old female was admitted in a Swiss hospital for induction chemotherapy of acute myeloid leukemia. A chest CT performed during the neutropenic phase identified three well-circumscribed lung lesions consistent with invasive fungal infection, along with a positive 1,3-beta-d-glucan assay in serum. A transbronchial biopsy of the lung lesions revealed large occasionally septate hyphae. A Conidiobolus spp. was detected by direct 18S rDNA in the tissue biopsy and subsequently identified at species level as C. pachyzygosporus by 28S rDNA sequencing. The infection was cured after isavuconazole therapy, recovery of the immune system and surgical resection of lung lesions. CONCLUSIONS: This is the first description of C. pachyzygosporus as human pathogen and second case report of invasive conidiobolomycosis from a European country.


Assuntos
Conidiobolus/genética , Leucemia Mieloide Aguda/complicações , Pneumopatias Fúngicas/complicações , Pneumopatias Fúngicas/diagnóstico , Zigomicose/complicações , Zigomicose/diagnóstico , Idoso , Antifúngicos/uso terapêutico , Biópsia , Conidiobolus/isolamento & purificação , DNA Fúngico/genética , DNA Ribossômico/genética , Feminino , Humanos , Hifas/isolamento & purificação , Hospedeiro Imunocomprometido , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/patologia , Nitrilos/uso terapêutico , Piridinas/uso terapêutico , Suíça , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Triazóis/uso terapêutico , Zigomicose/tratamento farmacológico , Zigomicose/patologia
5.
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
6.
Mycoses ; 63(6): 528-534, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-547397

RESUMO

OBJECTIVES: Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus disease 19 (COVID-19) associated invasive aspergillosis at a single centre in Cologne, Germany. METHODS: A retrospective chart review of all patients with COVID-19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany. RESULTS: COVID-19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS. CONCLUSION: Clinicians caring for patients with ARDS due to COVID-19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co-infection.


Assuntos
Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Aspergilose Pulmonar/complicações , Síndrome do Desconforto Respiratório do Adulto/complicações , Idoso , Antifúngicos/uso terapêutico , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/virologia , Infecções por Coronavirus/diagnóstico por imagem , Feminino , Alemanha , Hemorragia/etiologia , Hospitais de Ensino , Humanos , Unidades de Terapia Intensiva , Pneumopatias/etiologia , Masculino , Mananas/análise , Metapneumovirus/isolamento & purificação , Pessoa de Meia-Idade , Nitrilos/uso terapêutico , Pandemias , Infecções por Paramyxoviridae/etiologia , Pneumonia Viral/diagnóstico por imagem , Aspergilose Pulmonar/diagnóstico por imagem , Piridinas/uso terapêutico , Síndrome do Desconforto Respiratório do Adulto/diagnóstico por imagem , Estudos Retrospectivos , Tórax/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Triazóis/uso terapêutico , Voriconazol/uso terapêutico
7.
Mycoses ; 63(6): 528-534, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-125102

RESUMO

OBJECTIVES: Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus disease 19 (COVID-19) associated invasive aspergillosis at a single centre in Cologne, Germany. METHODS: A retrospective chart review of all patients with COVID-19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany. RESULTS: COVID-19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS. CONCLUSION: Clinicians caring for patients with ARDS due to COVID-19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co-infection.


Assuntos
Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Aspergilose Pulmonar/complicações , Síndrome do Desconforto Respiratório do Adulto/complicações , Idoso , Antifúngicos/uso terapêutico , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/virologia , Infecções por Coronavirus/diagnóstico por imagem , Feminino , Alemanha , Hemorragia/etiologia , Hospitais de Ensino , Humanos , Unidades de Terapia Intensiva , Pneumopatias/etiologia , Masculino , Mananas/análise , Metapneumovirus/isolamento & purificação , Pessoa de Meia-Idade , Nitrilos/uso terapêutico , Pandemias , Infecções por Paramyxoviridae/etiologia , Pneumonia Viral/diagnóstico por imagem , Aspergilose Pulmonar/diagnóstico por imagem , Piridinas/uso terapêutico , Síndrome do Desconforto Respiratório do Adulto/diagnóstico por imagem , Estudos Retrospectivos , Tórax/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Triazóis/uso terapêutico , Voriconazol/uso terapêutico
8.
Ann Hematol ; 99(6): 1241-1249, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32307568

RESUMO

Patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) can be effectively treated with tyrosine kinase inhibitors (TKIs) and achieve a lifespan similar to the general population. The success of TKIs, however, requires long-term and sometimes lifelong treatment; thus, patient-assessed health-related quality of life (HRQoL) has become an increasingly important parameter for treatment selection. Bosutinib is a TKI approved for CP CML in newly diagnosed adults and in those resistant or intolerant to prior therapy. In the Bosutinib Trial in First-Line Chronic Myelogenous Leukemia Treatment (BFORE), bosutinib demonstrated a significantly higher major molecular response rate compared with imatinib, with maintenance of HRQoL (measured by the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaire), after 12 months of first-line treatment. We examined relationships between molecular response (MR) and HRQoL. MR values were represented by a log-reduction scale (MRLR; a continuous variable). A repeated-measures longitudinal model was used to estimate the relationships between MRLR as a predictor and each FACT-Leu domain as an outcome. Effect sizes were calculated to determine strength of effects and allow comparisons across domains. The majority of FACT-Leu domains (with the exception of social well-being and physical well-being) demonstrated a significant relationship with MRLR (p < 0.05). Our results showed variable impact of clinical improvement on different dimensions of HRQoL. For patients who achieved MR5, emotional well-being and leukemia-specific domains showed the greatest improvement, with medium differences in effect sizes, whereas social well-being and physical well-being had the weakest relationship with MR.


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/psicologia , Nitrilos/uso terapêutico , Qualidade de Vida/psicologia , Quinolinas/uso terapêutico , Humanos , Leucemia Mieloide de Fase Crônica/sangue , Resultado do Tratamento
9.
Medicine (Baltimore) ; 99(17): e19822, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332626

RESUMO

Previous studies have shown androgen receptor (AR) is associated with the occurrence, development, recurrence, metastasis, and prognosis of triple negative breast cancer (TNBC). More and more experts have noticed that AR signaling pathway plays an important role in the occurrence and development of TNBC. The purpose of this study is to detect the inhibitory efficacy and mechanism of Bicalutamide on the proliferation and invasion of TNBC cells.MDA-MB-231 cells of human breast cancer cells were treated with 0, 25, 100 µmol/L of Bicalutamide, cell proliferation assay was performed to assess cell proliferation viability by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide assay and cell invasion was evaluated by Transwell assay. Meanwhile, flow cytometric analysis and western blotting were performed to investigate the mechanism of Bicalutamide on the proliferation and invasion of MDA-MB-231 cells.Bicalutamide could efficiently inhibit the proliferation and invasion of MDA-MB-231 cells in a dose-dependent manner. In addition, Bicalutamide could significantly induce the cell cycle arrest at G0/G1 phase and decrease the protein expression of AR, cyclin D1, matrix metalloprotease-2 (MMP-2), and matrix metalloprotease-9 (MMP-9).The present study indicated the Bicalutamide inhibited the proliferation and invasion process of triple negative breast cancer cells by targeting AR signaling pathway and down-regulating MMP-2/-9 protein expression levels.


Assuntos
Anilidas/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Nitrilos/uso terapêutico , Compostos de Tosil/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Anilidas/farmacologia , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo/métodos , Humanos , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Nitrilos/farmacologia , Sais de Tetrazólio , Compostos de Tosil/farmacologia , Neoplasias de Mama Triplo Negativas/fisiopatologia
10.
Mycoses ; 63(6): 528-534, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32339350

RESUMO

OBJECTIVES: Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus disease 19 (COVID-19) associated invasive aspergillosis at a single centre in Cologne, Germany. METHODS: A retrospective chart review of all patients with COVID-19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany. RESULTS: COVID-19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS. CONCLUSION: Clinicians caring for patients with ARDS due to COVID-19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co-infection.


Assuntos
Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Aspergilose Pulmonar/complicações , Síndrome do Desconforto Respiratório do Adulto/complicações , Idoso , Antifúngicos/uso terapêutico , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/virologia , Infecções por Coronavirus/diagnóstico por imagem , Feminino , Alemanha , Hemorragia/etiologia , Hospitais de Ensino , Humanos , Unidades de Terapia Intensiva , Pneumopatias/etiologia , Masculino , Mananas/análise , Metapneumovirus/isolamento & purificação , Pessoa de Meia-Idade , Nitrilos/uso terapêutico , Pandemias , Infecções por Paramyxoviridae/etiologia , Pneumonia Viral/diagnóstico por imagem , Aspergilose Pulmonar/diagnóstico por imagem , Piridinas/uso terapêutico , Síndrome do Desconforto Respiratório do Adulto/diagnóstico por imagem , Estudos Retrospectivos , Tórax/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Triazóis/uso terapêutico , Voriconazol/uso terapêutico
11.
Bull Cancer ; 107(4): 506-516, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32145961

RESUMO

A subgroup of androgen receptor-expressing tumors represents approximately 30 % of all triple negative tumors. The androgen receptor and its signaling pathways have a central biological role in this tumor entity. These triple negative androgen receptor-positive tumors occur in older patients and do not appear to have a better prognosis compared to other triple negative tumors. In addition to androgen receptor-expression, these tumors are genomically characterized by a high frequency of PIK3CA activating mutation. Three clinical trials reported efficacy data for anti-androgens (bicalutamide, abiraterone acetate and enzalutamide) based on strong preclinical rationale. These trials report clinical benefit rates in about one in five patients. These encouraging but still limited results make a case for the identification of predictive response factors and therapeutic combinations to improve response rates. This review will provide an update on the biological and clinical knowledge of this tumoral subgroup that opens the way to non-cytotoxic anti-androgen therapies.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Doenças Raras/metabolismo , Receptores Androgênicos/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Acetato de Abiraterona/uso terapêutico , Fatores Etários , Idoso , Anilidas/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/genética , Ensaios Clínicos como Assunto , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Previsões , Humanos , Mutação , Nitrilos/uso terapêutico , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Prognóstico , Doenças Raras/tratamento farmacológico , Transdução de Sinais , Compostos de Tosil/uso terapêutico
12.
J Fr Ophtalmol ; 43(4): 330-333, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32151474

RESUMO

Acanthamoeba keratitis due to a genus of free-living amoebae is a severe corneal infection. Treatment of this disease is based on the combined use of antiseptics and other drugs, including azoles. We tested isavuconazole, the latest marketed azole, in vitro, against A. castellanii, A. lenticulata and A. hatchetti. Our results show that isavuconazole presents slight amoebistatic activity against A. castellanii trophozoites but no cysticidal activity. Isavuconazole could be used only in association for management of AK due to A. castellanii.


Assuntos
Ceratite por Acanthamoeba/parasitologia , Acanthamoeba/efeitos dos fármacos , Nitrilos/farmacologia , Piridinas/farmacologia , Triazóis/farmacologia , Acanthamoeba/classificação , Acanthamoeba/crescimento & desenvolvimento , Acanthamoeba/fisiologia , Ceratite por Acanthamoeba/tratamento farmacológico , Acanthamoeba castellanii/efeitos dos fármacos , Acanthamoeba castellanii/crescimento & desenvolvimento , Acanthamoeba castellanii/fisiologia , Animais , Relação Dose-Resposta a Droga , Humanos , Nitrilos/uso terapêutico , Encistamento de Parasitas/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Trofozoítos/efeitos dos fármacos
13.
Leukemia ; 34(4): 966-984, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32127639

RESUMO

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Compostos de Anilina/uso terapêutico , Tomada de Decisão Clínica , Conferências de Consenso como Assunto , Dasatinibe/uso terapêutico , Gerenciamento Clínico , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Expressão Gênica , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Expectativa de Vida/tendências , Monitorização Fisiológica , Nitrilos/uso terapêutico , Pirimidinas/uso terapêutico , Qualidade de Vida , Quinolinas/uso terapêutico , Análise de Sobrevida
14.
Vet Parasitol ; 279: 109039, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32044501

RESUMO

Ctenocephalides felis infestations outbreak is documented as a welfare and production limiting disease in neonatal calves in eastern New South Wales, Australia. Due to the calves' discomfort, the first objective was to relieve the calves from the large burden of fleas. The affected neonatal 0-4 week old calves showed dull and quiet demeanour, with the geometric mean of body condition score (BCS) 2.67 (2-4) and geometric mean burden 41.51 (15-75) of fleas collected over 3 min. Deltamethrin pour-on (Arrest Easy-Dose, Virbac Animal Health, Australia) registered for treatment of lice and flies on cattle in Australia was evaluated for control effect of the cat flea (C. felis) on cattle. The fleas were identified morphologically as being C. felis which was confirmed by sequencing cytochrome c oxidase I gene (cox1). We report successful improvement of welfare and reduction of flea counts post application of pour-on deltamethrin on the property. In the absence of registered flea product for cattle in Australia, deltamethrin pour-on product is a suitable option, because of its registration for control of lice and flies on cattle.


Assuntos
Antiparasitários/uso terapêutico , Doenças dos Bovinos/prevenção & controle , Ctenocephalides/fisiologia , Infestações por Pulgas/veterinária , Nitrilos/uso terapêutico , Piretrinas/uso terapêutico , Animais , Bovinos , Doenças dos Bovinos/parasitologia , Indústria de Laticínios , Infestações por Pulgas/parasitologia , Infestações por Pulgas/prevenção & controle , New South Wales
15.
Am J Physiol Renal Physiol ; 318(3): F576-F588, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961716

RESUMO

Nephrotoxicity is a known clinical complication of cisplatin that limits the use of this potent antitumor drug. Cyclic nucleotide phosphodiesterases (PDEs) play complex roles in physiology and pathology. PDE4, which is a member of the PDE family, has four subtypes (PDE4A-PDE4D), and PDE4B plays an important role in inflammation. Thus, in the present study, we investigated the effect of PDE4/PDE4B inhibition on renal function and inflammation in a cisplatin nephrotoxicity model. In mice, cisplatin enhanced mRNA and protein expression of PDE4B in renal tubules. After treatment with the PDE4 inhibitor cilomilast, cisplatin-induced renal dysfunction, renal tubular injury, tubular cell apoptosis, and inflammation were all improved. Next, after silencing PDE4B in vivo, we observed a protective effect against cisplatin nephrotoxicity similar to that of the PDE4 inhibitor. In vitro, cisplatin-induced renal tubular cell death was strikingly ameliorated by the PDE4 inhibitor and PDE4B knockdown along with the blockade of the inflammatory response. Considering the known roles of some cell survival pathways in antagonizing insults, we examined levels of PDE4-associated proteins sirtuin 1, phosphatidylinositol 3-kinase, and phosphorylated AKT in cisplatin-treated renal tubular cells with or without cilomilast treatment. Strikingly, cisplatin treatment downregulated the expression of the above proteins, and this effect was largely abolished by the PDE4 inhibitor. Together, these findings indicate the beneficial role of PDE4/PDE4B inhibition in treating cisplatin nephrotoxicity, possibly through antagonizing inflammation and restoring cell survival signaling pathways.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Cisplatino/toxicidade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ácidos Cicloexanocarboxílicos/farmacologia , Inflamação/tratamento farmacológico , Nitrilos/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Lesão Renal Aguda/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Células Cultivadas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Ácidos Cicloexanocarboxílicos/uso terapêutico , Células Epiteliais/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Túbulos Renais/citologia , Masculino , Camundongos , Nitrilos/uso terapêutico , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo
17.
Ann Hematol ; 99(2): 359-361, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31872359
18.
Biomed Pharmacother ; 121: 109660, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31733581

RESUMO

Topiroxostat is a selective xanthine oxidoreductase (XOR) inhibitor for the management of hyperuricemia in patients with or without gout. In this work, we aim to employ the physiologically based pharmacokinetic (PBPK) model with the drug-target residence time model to predict and characterize both the pharmacokinetics (PK) and pharmacodynamics (PD) of topiroxostat in humans. The plasma concentration-time profile of topiroxostat was simulated based on drug properties and human physiology parameters. The predictive power of this PBPK model was then demonstrated by comparison of stimulated to observed pharmacokinetic parameters. The utility of the model was further demonstrated through predicting the oral absorption and disposition characteristics of topiroxostat in humans. Finally, by combining the PBPK model and the drug-target residence time model, we successfully predicted the target occupancy and built the relationship between PK and PD using in vitro, in vivo and in silico information. The results showed that topiroxostat exhibited significant in vivo pharmacological activity even after the complete clearance of this drug from the liver (target site), which may be due to the long residence time of the binary topiroxostat-XOR complex. This work may be helpful to guide future investigations of topiroxostat and also provides a novel strategy for PK/PD studies.


Assuntos
Interações Medicamentosas/fisiologia , Nitrilos/farmacocinética , Nitrilos/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Adulto , Atorvastatina/farmacocinética , Atorvastatina/uso terapêutico , Citocromo P-450 CYP3A/metabolismo , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Estudos de Avaliação como Assunto , Humanos , Lactonas/farmacocinética , Lactonas/uso terapêutico , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/metabolismo , Rabdomiólise/tratamento farmacológico , Rabdomiólise/metabolismo
19.
J Med Econ ; 23(1): 86-97, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31262225

RESUMO

Aims: To estimate the cost-effectiveness of isavuconazole compared with the standard of care, voriconazole, for the treatment of patients with invasive fungal infection disease when differential diagnosis of the causative pathogen has not yet been achieved at treatment initiation.Materials and methods: The economic model was developed from the perspective of the UK National Health Service (NHS) and used a decision-tree approach to reflect real-world treatment of patients with invasive fungal infection (IFI) prior to differential pathogen diagnosis. It was assumed that 7.8% of patients with IFI prior to differential pathogen diagnosis at treatment initiation actually had mucormycosis, and confirmation of pathogen identification was achieved for 50% of all patients during treatment. To extrapolate to a lifetime horizon, the model considered expected survival based on the patients' underlying condition. The model estimated the incremental costs (costs of drugs, laboratory analysis, hospitalization, and management of adverse events) and clinical outcomes (life-years (LYs) and quality-adjusted life-years (QALYs)) of first-line treatment with isavuconazole compared with voriconazole. The robustness of the results was assessed by conducting deterministic and probabilistic sensitivity analyses.Results: Isavuconazole delivered 0.48 more LYs and 0.39 more QALYs per patient at an incremental cost of £3,228, compared with voriconazole in the treatment of patients with IFI prior to differential pathogen diagnosis. This equates to an incremental cost-effectiveness ratio (ICER) of £8,242 per additional QALY gained and £6,759 per LY gained. These results were driven by a lack of efficacy of voriconazole in mucormycosis. Results were most sensitive to the mortality of IA patients and treatment durations.Conclusions: At a willingness to pay (WTP) threshold of £30,000 per additional QALY, the use of isavuconazole for the treatment of patients with IFI prior to differential pathogen diagnosis in the UK can be considered a cost-effective allocation of healthcare resources compared with voriconazole.


Assuntos
Antifúngicos/economia , Antifúngicos/uso terapêutico , Gastos em Saúde/estatística & dados numéricos , Infecções Fúngicas Invasivas/tratamento farmacológico , Nitrilos/economia , Nitrilos/uso terapêutico , Piridinas/economia , Piridinas/uso terapêutico , Triazóis/economia , Triazóis/uso terapêutico , Análise Custo-Benefício , Árvores de Decisões , Diagnóstico Diferencial , Recursos em Saúde/economia , Serviços de Saúde/economia , Serviços de Saúde/estatística & dados numéricos , Hospitalização/economia , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Modelos Econômicos , Honorários por Prescrição de Medicamentos/estatística & dados numéricos , Anos de Vida Ajustados por Qualidade de Vida , Medicina Estatal , Análise de Sobrevida , Incerteza , Reino Unido , Voriconazol/economia , Voriconazol/uso terapêutico
20.
Nagoya J Med Sci ; 81(4): 707-710, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31849389

RESUMO

Currently, the early introduction of new antiandrogens is popular for castration-resistant prostate cancer (CRPC). However, adverse events can be severe and their costs are high. Here, we present a patient with CRPC in whom flutamide controlled disease progression for 10 years. This case report shows that conventional alternative antiandrogens are cost effective and are still an important option for the treatment for CRPC.


Assuntos
Anilidas/uso terapêutico , Flutamida/uso terapêutico , Nitrilos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Compostos de Tosil/uso terapêutico , Idoso , Progressão da Doença , Humanos , Masculino , Temperatura
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