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1.
Ann Palliat Med ; 10(3): 2429-2438, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33440980

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is the causative agent of coronavirus disease 2019 (COVID-19). Lung lesions are considered to be the main damage caused by SARSCoV-2 infection. In addition, liver injury has also been reported to occur during the course of the disease in severe cases. However, the effect of antiviral treatment on liver injury in critically ill patients is not yet clear. METHODS: We retrospectively evaluated the effect of antiviral treatment and antiviral drug arbidol on liver injury in COVID-19 critically ill patients. Baseline characteristics were collected from patients who were admitted to intensive care units of Tongji Hospital in Wuhan, China, and confounders were balanced by propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses. RESULTS: Both the PSM (OR=2.77; 95% CI: 1.03, 7.48; P=0.045) and the IPTW-adjusted (OR=2.33; 95% CI: 1.02, 5.34; P=0.047) results showed that COVID-19 critically ill patients receiving antiviral treatment had a significantly higher risk of liver injury. However, arbidol treatment did not have a significant effect on liver injury (IPTW: OR=2.11; 95% CI: 0.79, 5.67; P=0.14). CONCLUSIONS: Our results show that although arbidol treatment does not seem to be significantly associated with liver injury complications, the overall use of antiviral drugs increases the risk of liver injury for critically ill patients with COVID-19. Antiviral drugs are widely used to treat COVID-19, but we recommend that for critically ill patients, antiviral treatment should be used with caution considering both effectiveness and potential adverse effects.


Assuntos
Antivirais/efeitos adversos , Indóis/efeitos adversos , Fígado/efeitos dos fármacos , Antivirais/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas , China , Estado Terminal , Humanos , Indóis/uso terapêutico , Fígado/patologia , Estudos Retrospectivos
2.
Lancet Respir Med ; 9(1): 96-106, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33412120

RESUMO

BACKGROUND: In the Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial, nintedanib reduced the rate of decline in forced vital capacity (FVC) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). Patients on stable treatment with mycophenolate for at least 6 months before randomisation could participate. The aim of this subgroup analysis was to examine the efficacy and safety of nintedanib by mycophenolate use at baseline. METHODS: The SENSCIS trial was a randomised, double-blind, placebo-controlled trial, in which patients with SSc-ILD were randomly assigned (1:1) to receive 150 mg of oral nintedanib twice daily or placebo for at least 52 weeks. In a prespecified subgroup analysis, we analysed the primary endpoint of rate of decline in FVC over 52 weeks by mycophenolate use at baseline. In a post-hoc analysis, we analysed the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted at week 52 (proposed minimal clinically important difference estimate for worsening of FVC in patients with SSc-ILD) in subgroups by mycophenolate use at baseline. Adverse events were reported in subgroups by mycophenolate use at baseline. Analyses were done in all participants who received at least one dose of study drug. We analysed the annual rate of decline in FVC using a random coefficient regression model (with random slopes and intercepts) including anti-topoisomerase I antibody status, age, height, sex, and baseline FVC as covariates and terms for baseline-by-time, treatment-by-subgroup, and treatment-by-subgroup-by-time interactions. SENSCIS is registered with ClinicalTrials.gov, NCT02597933, and is now complete. FINDINGS: Between Nov 30, 2015, and Oct 31, 2017, 819 participants were screened and 576 were enrolled, randomly assigned to, and treated with nintedanib (n=288) or placebo (n=288). 139 (48%) of 288 in the nintedanib group and 140 (49%) of 288 in the placebo group were taking mycophenolate at baseline. In patients taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -40·2 mL per year (SE 19·8) with nintedanib and -66·5 mL per year (19·3) with placebo (difference: 26·3 mL per year [95% CI -27·9 to 80·6]). In patients not taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -63·9 mL per year (SE 19·3) with nintedanib and -119·3 mL per year (19·0) with placebo (difference: 55·4 mL per year [95% CI 2·3 to 108·5]). We found no heterogeneity in the effect of nintedanib versus placebo on the annual rate of decline in FVC between the subgroups by mycophenolate use (p value for interaction=0·45). In a post-hoc analysis, the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted was lower with nintedanib than with placebo in both patients taking mycophenolate (40 [29%] of 138 vs 56 [40%] of 140; odds ratio 0·61 [0·37 to 1·01]) and those not taking mycophenolate (59 [40%] of 149 vs 70 [47%] of 148; 0·73 [0·46 to 1·16]) at baseline. The adverse event profile of nintedanib was similar between the subgroups. Diarrhoea, the most common adverse event, was reported in 106 (76%) of 139 patients in the nintedanib group and 48 (34%) of 140 in the placebo group among those taking mycophenolate at baseline, and in 112 (75%) of 149 in the nintedanib group and 43 (29%) of 148 in the placebo group among those not taking mycophenolate at baseline. Over the entire trial period, 19 patients died (ten in the nintedanib group and nine in the placebo group). One death in the nintedanib group was considered to be related to study drug. INTERPRETATION: Nintedanib reduced the progression of interstitial lung disease both in patients with SSc-ILD who were and were not using mycophenolate at baseline, with no heterogeneity in its treatment effect detected between the subgroups. The adverse event profile of nintedanib was similar in the subgroups by mycophenolate use. Our findings suggest that the combination of mycophenolate and nintedanib offers a safe treatment option for patients with SSc-ILD. More data are needed on the benefits of initial combination therapy versus a sequential approach to treatment of SSc-ILD. FUNDING: Boehringer Ingelheim.


Assuntos
Indóis/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Ácido Micofenólico/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Indóis/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Escleroderma Sistêmico/complicações , Resultado do Tratamento
3.
Anticancer Res ; 41(2): 551-556, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517260

RESUMO

Treatment of metastatic prostate cancer has evolved significantly over the past decade. Palliative therapy has, historically, consisted of androgen deprivation, chemotherapy and different radiation therapy approaches. More recently, breakthrough therapy with the use of poly-ADP-ribose polymerase (PARP) inhibitors has led to significant improvement in the outcome of patients with metastatic prostate cancer who harbor certain genetic mutations. This concise review focuses on the 3 PARP inhibitors that have shown activity in metastatic prostate cancer.


Assuntos
Indazóis/uso terapêutico , Indóis/uso terapêutico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Piperidinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Animais , Proteína BRCA1/genética , Proteína BRCA2/genética , Predisposição Genética para Doença , Humanos , Indazóis/efeitos adversos , Indóis/efeitos adversos , Masculino , Mutação , Metástase Neoplásica , PTEN Fosfo-Hidrolase/genética , Fenótipo , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Piperidinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Resultado do Tratamento
4.
J Toxicol Sci ; 45(9): 569-579, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879256

RESUMO

Indoxyl, a derivative of indole originating from tryptophan, may undergo phase-II sulfate-conjugation pathway, thereby forming indoxyl sulfate (IS) in vivo. We previously reported that IS, a well-known uremic toxin, can increase the intracellular oxidation level and decrease the phagocytic activity in a differentiated HL-60 human macrophage cell model. Using the same cell model, the current study aimed to investigate whether indole and indoxyl (the metabolic precursors of indoxyl and IS, respectively) may cause macrophage immune dysfunction. Results obtained indicated that intracellular oxidation level and cytotoxicity markedly increased upon treatment with indole and indoxyl, in comparison with IS. Incubation of the cells with indole and indoxyl also resulted in attenuated phagocytic activity. Human serum albumin (HSA)-binding assay confirmed that tryptophan and IS, but not indole and indoxyl, could selectively bind to the site II in HSA. Collectively, the results indicated that indole and indoxyl may strongly down-regulate the phagocytic immune function of macrophages, whereas IS, formed upon sulfate conjugation of indoxyl, may exhibit enhanced HSA-binding capability, thereby reducing the adverse effects of indoxyl.


Assuntos
Indóis/efeitos adversos , Macrófagos/imunologia , Macrófagos/metabolismo , Oxirredução/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Células HL-60 , Humanos , Indicã/metabolismo , Macrófagos/efeitos dos fármacos , Ligação Proteica , Albumina Sérica/metabolismo , Triptofano/metabolismo
5.
PLoS One ; 15(8): e0236935, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853277

RESUMO

BACKGROUND: Nintedanib is a multi-kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF); however, its efficacy and safety for patients with IPF and restricted pulmonary function remain unclear. Therefore, the objective of this study was to determine the efficacy and safety of nintedanib for patients with IPF and forced vital capacity (FVC) ≤ 50%. METHODS: This was a multi-center retrospective study performed by the Okayama Respiratory Disease Study Group. Patients were allocated into FVC ≤ 50% and FVC > 50% groups based on their predicted FVC. The primary endpoints were FVC changes from baseline after 6 and 12 months. RESULTS: 45 patients were eligible for the study. 18 patients had FVC ≤ 50%, and 27 patients had FVC > 50%. Overall, 31 and 19 patients underwent pulmonary function tests at 6 and 12 months after initiating nintedanib, respectively. FVC changes from baseline at 6 and 12 months after initiating nintedanib were comparable between the two groups. Adverse events were seen in all patients, and the rates of patients who discontinued nintedanib were also comparable (38.9% vs. 37.0%, p = 1.000). Multiple regression analysis showed that age and forced expiratory volume in 1 second (FEV1)/FVC were negatively correlated with changes in FVC at 6 months after initiating nintedanib. CONCLUSIONS: Our data suggest that nintedanib can be a useful agent for IPF patients, including those with a low FVC, and that age and FEV1/FVC are predictive markers for changes in FVC following nintedanib treatment.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/fisiopatologia , Indóis/uso terapêutico , Segurança , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Capacidade Vital
6.
J Allergy Clin Immunol ; 146(4): 786-789, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32710973

Assuntos
Antivirais/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/prevenção & controle , Hipersensibilidade a Drogas/etiologia , Fatores Imunológicos/efeitos adversos , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Corticosteroides/uso terapêutico , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/análogos & derivados , Amidas/administração & dosagem , Amidas/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/tratamento farmacológico , Hipersensibilidade a Drogas/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/administração & dosagem , Indóis/administração & dosagem , Indóis/efeitos adversos , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Índice de Gravidade de Doença
7.
Lancet Oncol ; 21(5): 710-722, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32359490

RESUMO

BACKGROUND: In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. METHODS: In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213. FINDINGS: Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0-33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0-17·4) in the rucaparib group versus 8·8 months (8·0-10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35-0·53]; p<0·0001), median TFST was 12·4 months (11·1-15·2) versus 7·2 months (6·4-8·6; HR 0·43 [0·35-0·52]; p<0·0001), median PFS2 was 21·0 months (18·9-23·6) versus 16·5 months (15·2-18·4; HR 0·66 [0·53-0·82]; p=0·0002), and median TSST was 22·4 months (19·1-24·5) versus 17·3 months (14·9-19·4; HR 0·68 [0·54-0·85]; p=0·0007). CFI, TFST, PFS2, and TSST were also significantly longer with rucaparib than placebo in the BRCA-mutant and homologous recombination-deficient cohorts. The most frequent treatment-emergent adverse event of grade 3 or higher was anaemia or decreased haemoglobin (80 [22%] patients in the rucaparib group vs one [1%] patient in the placebo group). Serious treatment-emergent adverse events were reported in 83 (22%) patients in the rucaparib group and 20 (11%) patients in the placebo group. Two treatment-related deaths have been previously reported in this trial; there were no new treatment-related deaths. INTERPRETATION: In these exploratory analyses over a median follow-up of more than 2 years, rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. FUNDING: Clovis Oncology.


Assuntos
Carcinoma/tratamento farmacológico , Indóis/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/patologia , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Indóis/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Platina/administração & dosagem , Platina/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Resultado do Tratamento
8.
Int J Clin Oncol ; 25(8): 1492-1498, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32447474

RESUMO

BACKGROUND: The ALTER 0303 study showed that anlotinib can significantly improve overall survival (OS) compared with the placebo in advanced non-small-cell lung cancer (NSCLC). Hand-foot syndrome (HFS) is a common anlotinib-related adverse event. The aim of this study was to assess the association of HFS with clinical benefit. METHODS: A subgroup analysis of patients treated with anlotinib from the ALTER 0303 study was performed. Our analysis assessed if the appearance of anlotinib-related HFS in the first 42 days (second-cycle HFS) and at any time could produce better clinical benefits. RESULTS: In this study, 294 patients were treated with anlotinib. Of which, 129 patients had HFS at any time, and 76 patients developed HFS in the first 2 cycles. Patients who received anlotinib and developed HFS had significantly prolonged OS, progression-free survival (PFS) compared to those who did not develop HFS in the first 2 cycles (13.5 vs 8.7 months, p = 0.001; adjusted hazard ratio (HR) 0.63 (95% confidence interval [CI] 0.44-0.89), p = 0.009; 5.8 vs 4.5 months, p = 0.001; adjusted HR, 0.59 [0.43-0.81], p = 0.001). The significant OS and PFS benefits for patients with HFS versus without were seen at any time (14.5 vs 7.3 months, p = 0.000; adjusted HR, 0.50 [0.36-0.67], p = 0.000; 5.8 vs 4.2 months, p = 0.000; adjusted HR, 0.49 [0.37-0.65], p = 0.000). In addition, the grade of severity of HFS was strongly correlated with OS (p = 0.000). CONCLUSION: Presence of HFS may be a potential clinical marker for the treatment of NSCLC with anlotinib.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Síndrome Mão-Pé/etiologia , Indóis/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Quinolinas/efeitos adversos , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Indóis/uso terapêutico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Quinolinas/uso terapêutico , Resultado do Tratamento
9.
Am J Trop Med Hyg ; 103(1): 378-393, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32314694

RESUMO

Malaria volunteer infection studies (VISs) accelerate new drug and vaccine development. In the induced blood-stage malaria (IBSM) model, volunteers are inoculated with erythrocytes infected with Plasmodium falciparum. Observations of elevated liver enzymes in the IBSM model with new chemical entities (NCEs) promoted an analysis of available data. Data were reviewed from eight IBSM studies of seven different NCEs, plus two studies with the registered antimalarial piperaquine conducted between June 2013 and January 2017 at QIMR Berghofer, Brisbane, Australia. Alanine aminotransferase (ALT) was elevated (> 2.5 times the upper limit of normal [×ULN]) in 20/114 (17.5%) participants. Of these, 8.9% (10/114) had moderate increases (> 2.5-5 × ULN), noted in seven studies of six different NCEs ± piperaquine or piperaquine alone, and 8.9% (10/114) had severe elevations (> 5 × ULN), occurring in six studies of six different NCEs ± piperaquine. Aspartate aminotransferase (AST) was elevated (> 2.5 × ULN) in 11.4% (13/114) of participants, across six of the 10 studies. Bilirubin was > 2 × ULN in one participant. Published data from other VIS models, using sporozoite inoculation by systemic administration or mosquito feeding, also showed moderate/severe liver enzyme elevations. In conclusion, liver enzyme elevations in IBSM studies are most likely multifactorial and could be caused by the model conditions, that is, malaria infection/parasite density and/or effective parasite clearance, or by participant-specific risk factors, acetaminophen administration, or direct hepatotoxicity of the test drug. We make recommendations that may mitigate the risk of liver enzyme elevations in future VISs and propose measures to assist their interpretation, should they occur.


Assuntos
Alanina Transaminase/metabolismo , Antimaláricos/efeitos adversos , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Voluntários Saudáveis , Malária Falciparum/tratamento farmacológico , Parasitemia/tratamento farmacológico , Acrilamidas/efeitos adversos , Adamantano/efeitos adversos , Adamantano/análogos & derivados , Adulto , Aminopiridinas/efeitos adversos , Aminoquinolinas/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Transfusão de Eritrócitos , Eritrócitos/parasitologia , Feminino , Compostos Ferrosos/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Indóis/efeitos adversos , Isoquinolinas/efeitos adversos , Masculino , Metalocenos/efeitos adversos , Peróxidos/efeitos adversos , Piperazinas/efeitos adversos , Plasmodium falciparum , Primaquina/efeitos adversos , Pirimidinas/efeitos adversos , Quinolinas/efeitos adversos , Compostos de Espiro/efeitos adversos , Sulfonas/efeitos adversos , Triazóis/efeitos adversos , Adulto Jovem
10.
Clin Microbiol Infect ; 26(7): 917-921, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32344167

RESUMO

OBJECTIVES: Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Umifenovir (Arbidol®) is an antiviral drug being used to treat influenza in Russia and China. This study aimed to investigate the effectiveness and safety of umifenovir for COVID-19. METHODS: A retrospective study was performed in a non-intensive care unit (ICU) ward in Jinyintan Hospital from 2 February 2020 to 20 March 2020. COVID-19 was confirmed by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assay of pharyngeal swab specimens. The confirmed patients were divided into the umifenovir group and the control group according to the use of umifenovir. The main outcomes were the rate of negative pharyngeal swab tests for SARS-CoV-2 within 1 week after admission and the time for the virus to turn negative. The negativity time of SARS-CoV-2 was defined as the first day of a negative test if the nucleic acid of SARS-CoV-2 was negative for two consecutive tests. RESULTS: A total of 81 COVID-19 patients were included, with 45 in the umifenovir group and 36 in the control group. Baseline clinical and laboratory characteristics were comparable between the two groups. Thirty-three out of 45 (73%) patients in the umifenovir group tested negative for SARS-CoV-2 within 7 days after admission, the number was 28/36 (78%) in the control group (p 0.19). The median time from onset of symptoms to SARS-CoV-2 turning negative was 18 days (interquartile range (IQR) 12-21) in the umifenovir group and 16 days (IQR 11-21) in the control group (p 0.42). Patients in the umifenovir group had a longer hospital stay than patients in the control group (13 days (IQR 9-17) vs 11 days (IQR 9-14), p 0.04). No deaths or severe adverse reactions were found in both groups. DISCUSSION: Umifenovir might not improve the prognosis or accelerate SARS-CoV-2 clearance in non-ICU patients. A randomized control clinical trial is needed to assess the efficacy of umifenovir.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Indóis/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Idoso , Feminino , Humanos , Indóis/efeitos adversos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do Tratamento
11.
J Infect ; 81(1): e21-e23, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32283143

RESUMO

Lopinavir/ritonavir and arbidol have been previously used to treat acute respiratory syndrome- coronavirus 2 (SARS-CoV-2) replication in clinical practice; nevertheless, their effectiveness remains controversial. In this study, we evaluated the antiviral effects and safety of lopinavir/ritonavir and arbidol in patients with the 2019-nCoV disease (COVID-19). Fifty patients with laboratory-confirmed COVID-19 were divided into two groups: including lopinavir/ritonavir group (34 cases) and arbidol group (16 cases). Lopinavir/ritonavir group received 400 mg/100mg of Lopinavir/ritonavir, twice a day for a week, while the arbidol group was given 0.2 g arbidol, three times a day. Data from these patients were retrospectively analyzed. The cycle threshold values of open reading frame 1ab and nucleocapsid genes by RT-PCR assay were monitored during antiviral therapy. None of the patients developed severe pneumonia or ARDS. There was no difference in fever duration between the two groups (P=0.61). On day 14 after the admission, no viral load was detected in arbidol group, but the viral load was found in 15(44.1%) patients treated with lopinavir/ritonavir. Patients in the arbidol group had a shorter duration of positive RNA test compared to those in the lopinavir/ritonavir group (P<0.01). Moreover, no apparent side effects were found in both groups. In conclusion, our data indicate that arbidol monotherapy may be superior to lopinavir/ritonavir in treating COVID-19.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Indóis/uso terapêutico , Lopinavir/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ritonavir/uso terapêutico , Adulto , Antivirais/administração & dosagem , Infecções por Coronavirus/virologia , Combinação de Medicamentos , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Lopinavir/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Estudos Retrospectivos , Ritonavir/efeitos adversos , Carga Viral
12.
Cancer Chemother Pharmacol ; 85(5): 907-915, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32266457

RESUMO

PURPOSE: Anlotinib is a novel oral multi-targeted receptor tyrosine kinase inhibitor, which selectively inhibits VEGFR2/3, FGFR1-4, PDGFR α/ß, c-kit, and Ret. It shows antitumor effect in patients with advanced refractory solid tumors. The detailed absorption, metabolism, and excretion pathways of anlotinib have not yet been fully investigated. METHODS: Six male patients were enrolled and divided into two groups. Group A (containing two patients) received 14.15 mg/80 µCi/subject [14C]-anlotinib hydrochloride. Group B (containing four patients) received 14.15 mg/120 µCi/subject [14C]-anlotinib hydrochloride. The blood, urine, and feces of all the six patients after orally administration of [14C]-anlotinib were collected. The absorption, metabolism, and excretion of [14C]-anlotinib were investigated, and the efficacy and safety of anlotinib were evaluated. RESULTS: In plasma, the average time to peak concentration (Tmax) of total radioactivity was 4.42 h and the average peak concentration (Cmax) of total radioactivity was 18.80 ng Eq./g. The average values of AUC0-last, AUC0-∞, and MRT0-t were 4071 h.ng Eq./g, 13,555 h.ng Eq./g, and 125 h, respectively. The average recovery of total radioactivity (TRA) in urine and feces was 62.03%, accounting for 48.52% and 13.51% in feces and urine of the total dosage, respectively. The parent drug, a carboxylic metabolite (M30), and mono-oxidation products (M46/M66) were major drug-related components in human plasma. Oxidative metabolism played the major role in drug clearance in human. The major metabolic pathways include oxidative deamination to M2, mono-oxidation to M1, and the formation of M30. Adverse events occurred in five patients and severe adverse events (SAE) occurred in one. Tumor response were evaluated as stable disease (SD) in three, partial response (PR) in one, and progressive disease (PD) in one of the patients, respectively. CONCLUSIONS: Anlotinib had a good pharmacokinetic profile with rapid absorption, long half-life, and extensive hepatic metabolism. The adverse events and efficacy were as expected.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Indóis , Neoplasias Renais/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinolinas , Sarcoma/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Neoplasias Colorretais/patologia , Monitoramento de Medicamentos/métodos , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/farmacocinética , Neoplasias Renais/patologia , Fígado/metabolismo , Masculino , Taxa de Depuração Metabólica , Desentoxicação Metabólica Fase I , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/farmacocinética , Sarcoma/patologia , Distribuição Tecidual , Resultado do Tratamento
13.
BMC Cancer ; 20(1): 215, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171277

RESUMO

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors are approved for the treatment of breast cancer susceptibility genes 1 and 2 (BRCA1/2) mutant ovarian and breast cancers, and are now being evaluated in metastatic castration-resistant prostate cancer (mCRPC). Reversion mutations that restore BRCA1/2 function have been shown to be responsible for resistance to platinum-based chemotherapy and PARP inhibitors, however there is no information on the sequential use of these agents in prostate cancer. CASE PRESENTATION: A patient with mCRPC associated with a germline BRCA2 mutation was sequentially treated with carboplatin and the PARP inhibitor rucaparib. Genomic profiling of the available baseline tumor and progression blood samples using next-generation sequencing panel tests identified polyclonal BRCA2 reversion mutations post carboplatin treatment but prior to rucaparib treatment. A total of 12 somatic reversion mutations were detected and ranged from small indels to larger deletions of up to 387 amino acids. These alterations are all predicted to restore the BRCA2 open reading frame and potentially protein function. The patient received limited benefit while on rucaparib, likely due to these reversion mutations observed prior to treatment. CONCLUSIONS: Here we report a case of a patient with prostate cancer who received a platinum agent and PARP inhibitor sequentially and in whom polyclonal BRCA2 reversion mutations were identified as the likely mechanism of acquired resistance to carboplatin and primary resistance to PARP inhibition. These findings suggest caution is warranted in sequencing these agents.


Assuntos
Proteína BRCA2/genética , Carboplatina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Genes BRCA2 , Mutação em Linhagem Germinativa/efeitos dos fármacos , Indóis/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Carboplatina/efeitos adversos , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Resultado do Tratamento
14.
Gynecol Oncol ; 157(2): 500-507, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32173049

RESUMO

BACKGROUND: Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease. METHODS: Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non­platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations. RESULTS: Non­platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non­platinum-based regimens. CONCLUSION: High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/economia , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Bevacizumab/economia , Carcinoma Epitelial do Ovário/economia , Análise Custo-Benefício , Custos de Medicamentos , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indazóis/economia , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/economia , Infusões Intravenosas , Cadeias de Markov , Modelos Estatísticos , Recidiva Local de Neoplasia/economia , Neoplasias Ovarianas/economia , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Ftalazinas/economia , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperazinas/economia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/economia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Qualidade de Vida , Estados Unidos
15.
Sci Rep ; 10(1): 2585, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066817

RESUMO

Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles.


Assuntos
Antineoplásicos/química , Indazóis/química , Indóis/química , Ftalazinas/química , Piperazinas/química , Piperidinas/química , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/química , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Sítios de Ligação , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Células HEK293 , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indóis/administração & dosagem , Indóis/efeitos adversos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Polifarmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Especificidade por Substrato
16.
PLoS One ; 15(1): e0227128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910240

RESUMO

INTRODUCTION: Parkinson's disease (PD) patients treated with pramipexole (PPX) and ropinirole (ROP) exhibit a higher risk of developing impulse control disorders (ICDs), including gambling disorder, compulsive shopping, and hypersexuality. The management of ICDs in PD is challenging, due to the limited availability of effective therapeutic alternatives or counteractive strategies. Here, we used a pharmacoepidemiological approach to verify whether the risk for PPX/ROP-associated ICDs in PD patients was reduced by drugs that have been posited to exert therapeutic effects on idiopathic ICDs-including atypical antipsychotics (AAs), selective serotonin reuptake inhibitors (SSRIs), and glutamatergic modulators (GMs). METHODS: To quantify the strength of the associations between PPX/ROP and other medications with respect to ICD risk, odds ratios (ORs) were calculated by multivariable logistic regression, adjusting for age, gender, marital status race, psychiatric comorbidities, and use of cabergoline and levodopa. RESULTS: A total of 935 patients were included in the analysis. Use of GMs, SSRIs, and AAs was not associated with a decreased ICD risk in PD patients treated with PPX/ROP; conversely, ICD risk was significantly increased in patients treated with either GMs (Adjusted Odds Ratio, ORa: 14.00 [3.58-54.44]) or SSRIs (ORa: 3.67 [1.07-12.59]). Results were inconclusive for AAs, as available data were insufficient to compute a reliable ORa. CONCLUSIONS: These results suggest that some of the key pharmacological strategies used to treat idiopathic ICD may not be effective for ICDs associated with PPX and ROP in PD patients. Future studies with larger cohorts are needed to confirm, validate, and extend these findings.


Assuntos
Antiparkinsonianos/efeitos adversos , Antipsicóticos/uso terapêutico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/prevenção & controle , Doença de Parkinson/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Idoso , Antiparkinsonianos/uso terapêutico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/tratamento farmacológico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/epidemiologia , Transtornos Disruptivos, de Controle do Impulso e da Conduta/etiologia , Feminino , Humanos , Doença Iatrogênica/epidemiologia , Doença Iatrogênica/prevenção & controle , Indóis/efeitos adversos , Indóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pramipexol/efeitos adversos , Pramipexol/uso terapêutico
17.
BMC Pulm Med ; 20(1): 3, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31914963

RESUMO

BACKGROUND: The two 52-week INPULSIS trials investigated nintedanib versus placebo in patients with IPF, FVC ≥50% predicted and DLco 30-79% predicted. The 24-week INSTAGE trial investigated nintedanib plus sildenafil versus nintedanib alone in patients with IPF and DLco ≤35% predicted. We used data from INPULSIS and INSTAGE to compare the effects of nintedanib in patients with IPF with less versus more severe impairment in gas exchange at baseline. METHODS: Analyses were conducted in patients treated with nintedanib alone in the INPULSIS and INSTAGE trials and in patients treated with placebo in the INPULSIS trials. Outcomes included the rate of decline in FVC over 24 weeks, the proportions of patients who had a confirmed or suspected idiopathic acute exacerbation over 24 weeks, deaths over 24 weeks, and adverse events. Analyses were descriptive. RESULTS: In total, 638 and 136 patients received nintedanib alone in the INPULSIS and INSTAGE trials, respectively, and 423 patients received placebo in the INPULSIS trials. Rates of FVC decline were - 52.3 and - 66.7 mL/24 weeks in patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and - 102.8 mL/24 weeks in patients treated with placebo in INPULSIS. Confirmed or suspected idiopathic acute exacerbations were reported in 0.6 and 3.7% of patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and 2.1% of patients treated with placebo in INPULSIS. Deaths occurred in 2.0, 11.0 and 1.9% of patients in these groups, respectively. Diarrhoea adverse events were reported in 52.5 and 48.5% of patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and 16.1% of patients treated with placebo in INPULSIS. CONCLUSIONS: Based on data from the INSTAGE and INPULSIS trials, nintedanib had a similar effect on FVC decline over 24 weeks, and a similar safety and tolerability profile, in patients with IPF and more versus less severe impairment in gas exchange. These data support the use of nintedanib in patients with IPF who have advanced disease. TRIAL REGISTRATION: INPULSIS (NCT01335464 and NCT01335477); INSTAGE (NCT02802345).


Assuntos
Inibidores Enzimáticos/administração & dosagem , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/administração & dosagem , Idoso , Progressão da Doença , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Capacidade Vital/efeitos dos fármacos
20.
Am J Respir Cell Mol Biol ; 62(5): 577-587, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31721618

RESUMO

Mesenchymal stem cell extracellular vesicles attenuate pulmonary hypertension, but their ability to reverse established disease in larger animal models and the duration and mechanism(s) of their effect are unknown. We sought to determine the efficacy and mechanism of mesenchymal stem cells' extracellular vesicles in attenuating pulmonary hypertension in rats with Sugen/hypoxia-induced pulmonary hypertension. Male rats were treated with mesenchymal stem cell extracellular vesicles or an equal volume of saline vehicle by tail vein injection before or after subcutaneous injection of Sugen 5416 and exposure to 3 weeks of hypoxia. Pulmonary hypertension was assessed by right ventricular systolic pressure, right ventricular weight to left ventricle + septum weight, and muscularization of peripheral pulmonary vessels. Immunohistochemistry was used to measure macrophage activation state and recruitment to lung. Mesenchymal stem cell extracellular vesicles injected before or after induction of pulmonary hypertension normalized right ventricular pressure and reduced right ventricular hypertrophy and muscularization of peripheral pulmonary vessels. The effect was consistent over a range of doses and dosing intervals and was associated with lower numbers of lung macrophages, a higher ratio of alternatively to classically activated macrophages (M2/M1 = 2.00 ± 0.14 vs. 1.09 ± 0.11; P < 0.01), and increased numbers of peripheral blood vessels (11.8 ± 0.66 vs. 6.9 ± 0.57 vessels per field; P < 0.001). Mesenchymal stem cell extracellular vesicles are effective at preventing and reversing pulmonary hypertension in Sugen/hypoxia pulmonary hypertension and may offer a new approach for the treatment of pulmonary arterial hypertension.


Assuntos
Vesículas Extracelulares/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Hipóxia/complicações , Indóis/efeitos adversos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Pirróis/efeitos adversos , Animais , Fibroblastos/metabolismo , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Ativação de Macrófagos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Músculo Liso/patologia , Neovascularização Fisiológica , Ratos Sprague-Dawley , Remodelação Vascular , Fator de von Willebrand/metabolismo
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