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1.
Nat Commun ; 12(1): 5371, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34508085

RESUMO

Konzo, a distinct upper motor neuron disease associated with a cyanogenic diet and chronic malnutrition, predominately affects children and women of childbearing age in sub-Saharan Africa. While the exact biological mechanisms that cause this disease have largely remained elusive, host-genetics and environmental components such as the gut microbiome have been implicated. Using a large study population of 180 individuals from the Democratic Republic of the Congo, where konzo is most frequent, we investigate how the structure of the gut microbiome varied across geographical contexts, as well as provide the first insight into the gut flora of children affected with this debilitating disease using shotgun metagenomic sequencing. Our findings indicate that the gut microbiome structure is highly variable depending on region of sampling, but most interestingly, we identify unique enrichments of bacterial species and functional pathways that potentially modulate the susceptibility of konzo in prone regions of the Congo.


Assuntos
Suscetibilidade a Doenças/microbiologia , Comportamento Alimentar , Microbioma Gastrointestinal/fisiologia , Manihot/efeitos adversos , Doença dos Neurônios Motores/microbiologia , Criança , República Democrática do Congo/epidemiologia , Fezes/microbiologia , Feminino , Humanos , Manihot/química , Metagenômica , Doença dos Neurônios Motores/epidemiologia , Nitrilas/efeitos adversos
2.
West Afr J Med ; 38(8): 756-761, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34503324

RESUMO

BACKGROUND: The use of fixed dose combination oral antidiabetic drugs (OADs) in the therapeutic management of type 2 diabetes mellitus (DM) patients is becoming popular among clinicians. Reduced pill burden with fixed combination OADs is generally perceived to improve adherence and efficacy. The aim of this study was to compare the efficacy, tolerability and side effects (SEs) profile of vildagliptin-metformin (VM) combination with metformin-glibenclamide (MG) combination in type 2 DM patients at the Aminu Kano Teaching Hospital (AKTH). METHODS: A descriptive prospective open-labeled comparative out-patient study of type 2 DM patients spanning over three months with 60 Patients assigned to two treatment groups - VM (Group 1) and MG (Group 2) of 30 patients each. Parameters measured at baseline, 6 weeks and 12 weeks of study included demographic and anthropometric data; fasting plasma glucose (FPG) level; 2-hour post-prandial (2-hrPPG) glucose; liver function tests (LFTs); Electrolyte, Urea and Creatinine (EUCr); and fasting plasma lipids. Glycated haemoglobin (HbA1c) was measured at baseline and at 12 weeks of the study. A p-value of <0.05 was considered to be significant. RESULTS: There was improvement in FPG, 2hr PPG, HbA1c in all subjects in both groups at the end of the study (6.44±0.79mmol/ l, 8.80±1.16mmol/l and 7.22±1.20% respectively in group 1(VM); and 6.40±0.83mmol/l, 9.29±1.39 and 7.25±0.96% respectively for group 2(MG). There was a significant improvement in body mass index (BMI) of subjects in group 1 (30.02±4.16 at baseline, 29.71±4.12 at study end) compared to those in group 2 (31.98±6.32 at baseline, 32.62±6.30 at study end), p=0.04. At the end of the study, the efficacy of VM (HbA1C-7.22±1.20%) was comparable to that of MG (HbA1c-7.25±0.96), P=0.92. The tolerability of MG (attrition rate 6.7%) was better than that of VM (attrition rate 13%), although this difference was not statistically significant P=0.16. The subjects on VM experienced more gastrointestinal (GIT) side effects compared to those on MG. The major SEs experienced by those on MG were hypoglycaemia and weight gain. VM was less tolerated and had more GIT side effects than MG. CONCLUSION: The use of single pill combination oral antidiabetic medications is associated with improved efficacy.


Assuntos
Adamantano , Diabetes Mellitus Tipo 2 , Metformina , Adamantano/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Humanos , Metformina/efeitos adversos , Nigéria , Nitrilas/efeitos adversos , Estudos Prospectivos , Pirrolidinas/efeitos adversos , Vildagliptina/uso terapêutico
3.
Muscle Nerve ; 64(4): 504-508, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34322897

RESUMO

INTRODUCTION/AIMS: Perampanel, a selective noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist, is capable of slowing the progression of the amyotrophic lateral sclerosis (ALS) phenotype and increasing the number of anterior horn cells in transgenic mice. Trials of perampanel in epilepsy showed a favorable tolerability profile. In this study we aimed to determine the tolerability and safety of perampanel in patients with ALS. METHODS: Enrolled subjects were started on 2 mg/day of perampanel and the dose was increased by 2 mg/day every week to a maximum dose of 8 mg/day. Our primary outcome measure was tolerability, which was evaluated by monitoring adverse events. The secondary outcome measure was clinical progression, assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and spirometry. RESULTS: Six participants were enrolled. All had adverse events, mostly behavioral. Two completed the trial and the other four withdrew due to adverse events. All participants reported resolution of these events after discontinuation of the drug. The trial was halted due to the large number of adverse events. DISCUSSION: The use of perampanel in this study of ALS was limited by its poor tolerability.


Assuntos
Agressão/efeitos dos fármacos , Agressão/psicologia , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/psicologia , Nitrilas/efeitos adversos , Piridonas/efeitos adversos , Sonolência , Adulto , Idoso , Esclerose Amiotrófica Lateral/diagnóstico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Projetos Piloto , Comportamento Problema/psicologia , Piridonas/uso terapêutico
4.
Eur J Pharmacol ; 906: 174233, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34111397

RESUMO

Dihydroorotate dehydrogenase (DHODH) is rate-limiting enzyme in biosynthesis of pyrimidone which catalyzes the oxidation of dihydro-orotate to orotate. Orotate is utilized in the biosynthesis of uridine-monophosphate. DHODH inhibitors have shown promise as antiviral agent against Cytomegalovirus, Ebola, Influenza, Epstein Barr and Picornavirus. Anti-SARS-CoV-2 action of DHODH inhibitors are also coming up. In this review, we have reviewed the safety and efficacy of approved DHODH inhibitors (leflunomide and teriflunomide) against COVID-19. In target-centered in silico studies, leflunomide showed favorable binding to active site of MPro and spike: ACE2 interface. In artificial-intelligence/machine-learning based studies, leflunomide was among the top 50 ligands targeting spike: ACE2 interaction. Leflunomide is also found to interact with differentially regulated pathways [identified by KEGG (Kyoto Encyclopedia of Genes and Genomes) and reactome pathway analysis of host transcriptome data] in cogena based drug-repurposing studies. Based on GSEA (gene set enrichment analysis), leflunomide was found to target pathways enriched in COVID-19. In vitro, both leflunomide (EC50 41.49 ± 8.8 µmol/L) and teriflunomide (EC50 26 µmol/L) showed SARS-CoV-2 inhibition. In clinical studies, leflunomide showed significant benefit in terms of decreasing the duration of viral shredding, duration of hospital stay and severity of infection. However, no advantage was seen while combining leflunomide and IFN alpha-2a among patients with prolonged post symptomatic viral shredding. Common adverse effects of leflunomide were hyperlipidemia, leucopenia, neutropenia and liver-function alteration. Leflunomide/teriflunomide may serve as an agent of importance to achieve faster virological clearance in COVID-19, however, findings needs to be validated in bigger sized placebo controlled studies.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Crotonatos/farmacologia , Inibidores Enzimáticos/farmacologia , Hidroxibutiratos/farmacologia , Leflunomida/farmacologia , Nitrilas/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Toluidinas/farmacologia , Animais , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Crotonatos/efeitos adversos , Crotonatos/uso terapêutico , Reposicionamento de Medicamentos , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Humanos , Hidroxibutiratos/efeitos adversos , Hidroxibutiratos/uso terapêutico , Leflunomida/efeitos adversos , Leflunomida/uso terapêutico , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Toluidinas/efeitos adversos , Toluidinas/uso terapêutico
5.
Expert Opin Drug Saf ; 20(7): 741-749, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34114527

RESUMO

INTRODUCTION: Prostate cancer (PC) is the most common cancer in North American men. Advanced PC is incurable. The androgen receptor antagonist enzalutamide is used to manage advanced PC, often over a period of months or years; it is therefore important to evaluate the safety profile of enzalutamide. AREAS COVERED: This literature review presents safety data from pivotal trials and real-world data studies of enzalutamide in patients with advanced PC, including metastatic hormone-sensitive prostate cancer (mHSPC), nonmetastatic castration-resistant prostate cancer (nmCRPC), and metastatic castration-resistant prostate cancer (mCRPC). A large body of evidence supports the maintenance or improvement in the health-related quality of life (HRQoL) afforded by enzalutamide treatment in patients with mHSPC, nmCRPC, or chemotherapy-naïve mCRPC, as well as improvement in the HRQoL in patients with later-stage symptomatic mCRPC. Efficacy data from clinical trials are also briefly discussed. EXPERT OPINION: We aim to provide clinicians with a better understanding of how to properly interpret enzalutamide clinical trial safety data. This knowledge may help clinicians guide their patients with PC to achieve optimal clinical benefit from enzalutamide therapy, and to properly manage their patients to mitigate any potential risk.


Assuntos
Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Nitrilas/administração & dosagem , Feniltioidantoína/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antineoplásicos/efeitos adversos , Benzamidas/efeitos adversos , Humanos , Masculino , Nitrilas/efeitos adversos , Feniltioidantoína/efeitos adversos , Neoplasias da Próstata/patologia , Qualidade de Vida
6.
J Urol ; 206(2): 298-307, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33818140

RESUMO

PURPOSE: No published head-to-head randomized trials have compared the safety and efficacy of darolutamide vs apalutamide or enzalutamide in nonmetastatic castration-resistant prostate cancer. This study compares prespecified adverse events and metastasis-free survival associated with darolutamide vs apalutamide, and darolutamide vs enzalutamide, via matching-adjusted indirect comparisons. MATERIALS AND METHODS: Individual patient data from the phase III ARAMIS trial (NPLACEBO=553; NDAROLUTAMIDE=943) were selected and reweighted to match the inclusion criteria and baseline characteristics published for the phase III SPARTAN (NPLACEBO=401; NAPALUTAMIDE=806) and PROSPER (NPLACEBO=468; NENZALUTAMIDE=933) trials. Only baseline factors consistently reported across trials were included as matching covariates. Both indirect comparisons matched on age, prostate specific antigen level and doubling time, Eastern Cooperative Oncology Group performance status, Gleason score, and bone-sparing agent use. Darolutamide vs apalutamide also matched on prior surgery and darolutamide vs enzalutamide also matched on region. Risk differences and odds ratios were calculated for adverse events and hazard ratios for metastasis-free survival. RESULTS: No differences in metastasis-free survival hazard ratios were found after matching in either comparison. However, fall, fracture and rash rates were statistically significantly lower in favor of darolutamide vs apalutamide. Fall, dizziness, mental impairment, fatigue and severe fatigue rates were statistically significantly lower in favor of darolutamide vs enzalutamide. CONCLUSIONS: While metastasis-free survival did not differ across drugs in these cross-trial indirect comparisons, darolutamide showed a favorable safety and tolerability profile in prespecified adverse events vs apalutamide and enzalutamide. Consideration of these adverse events is important in clinical decision-making and treatment selection in nonmetastatic castration-resistant prostate cancer.


Assuntos
Benzamidas/efeitos adversos , Nitrilas/efeitos adversos , Feniltioidantoína/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirazóis/efeitos adversos , Tioidantoínas/efeitos adversos , Acidentes por Quedas/estatística & dados numéricos , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antagonistas de Receptores de Andrógenos/efeitos adversos , Benzamidas/administração & dosagem , Disfunção Cognitiva/induzido quimicamente , Tontura/induzido quimicamente , Exantema/induzido quimicamente , Fadiga/induzido quimicamente , Fraturas Espontâneas/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Feniltioidantoína/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/mortalidade , Pirazóis/administração & dosagem , Tioidantoínas/administração & dosagem
7.
Int J Hematol ; 114(1): 65-78, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33851349

RESUMO

Bosutinib is approved in the United States, Europe, Japan, and other countries for treatment of newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML), and CML resistant/intolerant to prior therapy. In the phase 3 BFORE trial (Clinicaltrials.gov, NCT02130557), patients were randomized 1:1 to first-line bosutinib or imatinib 400 mg once daily. We examined efficacy, safety, and patient-reported outcomes of bosutinib vs imatinib and pharmacokinetics of bosutinib in the Asian (n = 33 vs 34) and non-Asian (n = 235 vs 234) subpopulations of BFORE followed for at least 24 months. At the data cutoff date, 72.7 vs 66.7% of Asian and 70.6 vs 66.4% of non-Asian patients remained on treatment. The major molecular response rate at 24 months favored bosutinib vs imatinib among Asian (63.6 vs 38.2%) and non-Asian (60.9 vs 52.6%) patients, as did the complete cytogenetic response rate by 24 months (86.7 vs 76.7%, 81.5 vs 76.3%). Treatment-emergent adverse events in both subpopulations were consistent with the primary BFORE results. Trough bosutinib concentration levels tended to be higher in Asian patients. Health-related quality of life was maintained after 12 months of bosutinib in both subpopulations. These results support bosutinib as a first-line treatment option in Asian patients with CP CML.


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/efeitos adversos , Compostos de Anilina/sangue , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Ásia/epidemiologia , Feminino , Humanos , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Masculino , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Nitrilas/sangue , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Quinolinas/efeitos adversos , Quinolinas/sangue , Resultado do Tratamento , Adulto Jovem
8.
Epilepsia ; 62(3): 698-708, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33666943

RESUMO

OBJECTIVE: The objective was to summarize pregnancy and fetal/postnatal outcomes following maternal perampanel exposure using preclinical and clinical data, and to use physiologically based pharmacokinetic (PBPK) modeling to improve understanding of perampanel pharmacokinetics (PK) during pregnancy. METHODS: Preclinical developmental studies with perampanel were conducted in pregnant rats and rabbits. Clinical data were collated from the Eisai global perampanel safety database, comprising reports of perampanel exposure during pregnancy from routine clinical settings, interventional studies, and non-interventional post-marketing studies, searched for events coded to Medical Dictionary for Regulatory Activities (MedDRA) high-level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. A PBPK model was used to predict clinical perampanel PK throughout pregnancy. RESULTS: Preclinical studies indicated that perampanel may be linked with post-implantation loss and/or some specific physical development delays but not fertility and early embryonic development. As of August 31, 2018, 96 pregnancies in 90 women receiving perampanel had been reported. No concomitant medications were reported in 26 (28.9%) women taking perampanel. Overall, 43 pregnancies reached full term (all normal live births), 28 did not reach term (induced abortion, n = 18; spontaneous miscarriage, n = 6; incomplete spontaneous miscarriage, n = 2; premature delivery, n = 1; stillbirth [Fallot's tetralogy], n = 1), 18 were lost to follow-up, and seven were ongoing at data cut-off. Adverse events were reported in five full-term neonates (low Apgar score, n = 2; fatal neonatal aspiration, n = 1; cystic fibrosis and congenital deafness, n = 1; poor sucking reflex and shallow breathing, n = 1). PK simulations predicted perampanel exposure decreases throughout pregnancy and is up to four- and three-fold lower towards the end of pregnancy compared with non-pregnant women for total and unbound perampanel, respectively. SIGNIFICANCE: These data provide preliminary information on perampanel use during pregnancy and should be interpreted with caution. Further outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure.


Assuntos
Anticonvulsivantes/efeitos adversos , Epilepsia/complicações , Nitrilas/efeitos adversos , Complicações na Gravidez/tratamento farmacológico , Piridonas/efeitos adversos , Adulto , Animais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Relação Dose-Resposta a Droga , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Gravidez , Complicações na Gravidez/metabolismo , Resultado da Gravidez , Piridonas/farmacocinética , Piridonas/uso terapêutico , Coelhos , Ratos , Ratos Sprague-Dawley , Adulto Jovem
9.
Sci Rep ; 11(1): 6362, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737618

RESUMO

The purpose of this study was to investigate the effects of SLC22A2 808G>T polymorphism and trough concentrations (C0) of bosutinib on serum creatinine in 28 patients taking bosutinib. At 1, 3, 6, 12, 24, and 36 months after administration, analysis of bosutinib C0 and creatinine was performed at the same time of day. Significant correlations were observed between bosutinib C0 and the change rate of serum creatinine or the estimated glomerular filtration rate (eGFR; r = 0.328, P < 0.001 and r = - 0.315, P < 0.001, respectively). These correlations were particularly high in patients having the SLC22A2 808G/G genotype (r = 0.345 and r = - 0.329, respectively); however, in patients having the 808T allele, there were no significant differences. In multivariate analyses, the SLC22A2 808G/G genotype, patient age, bosutinib C0 and second-line or later bosutinib were independent factors influencing the change rate of creatinine. Bosutinib elevated serum creatinine through organic cation transporter 2 (OCT2). We observed a 20% increase in serum creatinine with a median bosutinib C0 of 63.4-73.2 ng/mL. Periodic measurement of serum creatinine after bosutinib therapy is necessary to avoid progression to severe renal dysfunction from simple elevation of creatinine mediated by OCT2 following bosutinib treatment.


Assuntos
Compostos de Anilina/administração & dosagem , Biomarcadores Farmacológicos/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilas/administração & dosagem , Transportador 2 de Cátion Orgânico/genética , Quinolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/efeitos adversos , Compostos de Anilina/sangue , Creatinina/sangue , Feminino , Genótipo , Taxa de Filtração Glomerular , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Nitrilas/sangue , Polimorfismo de Nucleotídeo Único/genética , Quinolinas/efeitos adversos , Quinolinas/sangue
10.
Expert Rev Clin Pharmacol ; 14(5): 535-544, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33685318

RESUMO

Introduction: Important changes in the treatment of prostate cancer have taken place in recent years. Non-metastatic castration-resistant prostate cancer (nmCRPC) has been clinically delineated. In this setting, three drugs have been approved in high-risk disease: apalutamide, enzalutamide and darolutamide.Areas covered:This manuscript aims to profile darolutamide, its clinical development, pharmacologic properties, efficacy and safety. We presented the results of published clinical studies, but we also investigated ongoing ones.Expert opinion: An indirect comparison with the other two aforementioned drugs emerged. While the clinical efficacy is comparable, the toxicity profile is different for darolutamide, resulting in greater tolerance. We must wait for the results of the trials that study darolutamide in hormone-sensitive disease, both in the metastatic phase and in the localized phase. Clinical experience will also be important to determine ever more personalized treatments for patients.


Assuntos
Antagonistas de Receptores de Andrógenos/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirazóis/administração & dosagem , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Humanos , Masculino , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Nitrilas/farmacologia , Feniltioidantoína/administração & dosagem , Feniltioidantoína/efeitos adversos , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/patologia , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Tioidantoínas/administração & dosagem , Tioidantoínas/efeitos adversos , Tioidantoínas/farmacologia
11.
Int J Radiat Oncol Biol Phys ; 110(5): 1416-1422, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33636278

RESUMO

PURPOSE: Androgen deprivation therapy (ADT) is often used as adjuvant treatment with radiation therapy (RT) for intermediate-risk prostate cancer. ADT is associated with multiple side effects, including weight gain, loss of libido, and hot flashes. In contrast, antiandrogen monotherapy has been generally better tolerated. This study aimed to assess the effectiveness of enzalutamide (an antiandrogen) monotherapy with RT for the treatment of intermediate-risk prostate cancer. METHODS AND MATERIALS: This trial was an open-label, phase 2 study of 6 months of enzalutamide monotherapy with external beam RT for intermediate-risk prostate cancer. Enzalutamide was initiated 2 months before external beam RT. The primary endpoint was prostate-specific antigen (PSA) response measured at the end of enzalutamide administration at the 6-month timepoint. Secondary endpoints included assessment of toxicity and changes in anthropomorphic body measurement, sexual function, and metabolism. The sample size was 64 patients. The hypothesis was that if ≥60% of the patients did not achieve a PSA nadir of ≤0.2 ng/mL, the study results would be deemed negative. RESULTS: The results met the prespecified endpoint for efficacy in that PSA values ≤0.2 ng/mL were observed in 49 of 64 patients (77%), and 60 of 64 patients (94%) had PSA values ≤0.5ng/mL. The most frequent adverse events were hypertension and gynecomastia. There were no changes in anthropomorphic body measurements and only modest erectile dysfunction. CONCLUSIONS: Using PSA response as an endpoint, enzalutamide monotherapy may be as effective as ADT in combination with external beam RT for patients with intermediate-risk prostate cancer, and it is associated with fewer side effects. Randomized trials comparing enzalutamide with ADT are justified.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Benzamidas/uso terapêutico , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Antagonistas de Androgênios/efeitos adversos , Androgênios/sangue , Benzamidas/efeitos adversos , Composição Corporal/efeitos dos fármacos , Distribuição da Gordura Corporal , Ginecomastia/induzido quimicamente , Humanos , Hipertensão/induzido quimicamente , Masculino , Nitrilas/efeitos adversos , Feniltioidantoína/efeitos adversos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Risco , Testosterona/sangue , Fatores de Tempo
12.
Prostate ; 81(3): 194-201, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33393676

RESUMO

BACKGROUND: To evaluate the possible major adverse cardiovascular events (MACE) associated with second-line hormonal therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: We performed a population-based real-world cohort study of 4962 prostate cancer patients between 2014 and 2017 utilizing the Chang Gung Research Database of Taiwan. The second-line hormonal therapies included enzalutamide and abiraterone acetate. The outcomes of interest were MACE, including acute coronary syndrome (ACS), ischemic stroke (IS), and heart failure (HF) events that resulted in hospitalization. Cox proportional-hazards models with inverse probability of treatment weighting (IPTW) with propensity scores were used. RESULTS: After IPTW, 288 patients were prescribed second-line hormonal therapy and 1575 received first-line androgen-deprivation therapy (ADT). Of all patients diagnosed with MACE, the event rates were 2.92% in the second-line hormonal group and 2.22% in the first-line ADT group. The mean follow-up period was 9.52 months for the second-line hormonal group. Patients who received second-line hormonal therapy exhibited a significantly increased risk for MACE (hazard ratio [HR]: 3.15; 95% confidence interval [CI]: 2.03-4.89), ACS (HR: 4.94; 95% CI: 2.36-10.33), and HF (HR: 2.83; 95% CI: 1.53-5.25), compared with the first-line ADT group, but a similar risk for IS was observed in both groups (HR: 1.70; 95% CI: 0.95-3.04). CONCLUSIONS: The real-world evidence study revealed increased risks for MACE in mCRPC patients receiving second-line hormonal therapy.


Assuntos
Doenças Cardiovasculares/epidemiologia , Metástase Neoplásica/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Acetato de Abiraterona/efeitos adversos , Acetato de Abiraterona/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Fatores de Risco , Inibidores da Síntese de Esteroides , Taiwan/epidemiologia , Resultado do Tratamento
13.
Breast Cancer Res Treat ; 185(3): 697-707, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33159633

RESUMO

BACKGROUND: Compared to tamoxifen, adjuvant treatment with aromatase inhibitors improves disease outcomes of postmenopausal women with hormone receptor-positive early breast cancer. In the international, randomized, double-blind BIG 1-98 trial, 8010 women were randomized to receive tamoxifen, letrozole, or sequential use of the agents for 5 years. With a focus on switching between agents, we investigated cardiovascular events over the entire 5-year treatment period. METHODS: Of the 6182 patients enrolled, 6144 started trial treatment and were included in this analysis. Adverse events occurring during study treatment until 30 days after cessation were considered. Eight cardiovascular event types were defined. Cumulative incidence of events were estimated using the Kaplan-Meier method, without consideration for competing events. Multivariable Cox models estimated hazard ratios (HR) with 95% confidence intervals (CI) for pairwise comparisons of treatment arms. RESULTS: While on study treatment, 6.5% of patients (n = 397) had any cardiac events reported; for 2.4%, the event was grades 3-5, of which 11 (0.2%) were grade 5. Letrozole monotherapy was associated with higher risk of grade 1-5 ischemic heart disease (HR = 1.81; 95% CI, 1.06-3.08) compared with tamoxifen monotherapy. Patients assigned sequential tamoxifen →letrozole (HR = 1.59; 95% CI, 0.92-2.74) or sequential letrozole → tamoxifen (HR = 1.20; 95% CI, 0.68-2.14) showed a lesser degree of risk elevation. Patients assigned to tamoxifen-containing regimens had significantly higher risk of grade 1-5 thromboembolic events (tamoxifen monotherapy HR = 2.10; 95% CI, 1.42-3.12; tamoxifen → letrozole HR = 1.96; 95% CI, 1.32-2.92; letrozole → tamoxifen HR = 1.56; 95% CI 1.03-2.35) as compared with patients assigned letrozole alone. CONCLUSION: When initiating or switching between adjuvant endocrine treatments in postmenopausal patients, age and medical history, with special attention to prior cardiovascular events, should be balanced with expected benefit of the treatment.


Assuntos
Neoplasias da Mama , Doenças Cardiovasculares , Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Incidência , Letrozol/efeitos adversos , Nitrilas/efeitos adversos , Pós-Menopausa , Tamoxifeno/efeitos adversos , Triazóis/uso terapêutico
15.
Mycoses ; 64(4): 445-456, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33355949

RESUMO

BACKGROUND: Isavuconazole is a broad-spectrum triazole for the treatment of invasive fungal disease (IFD). OBJECTIVE: To investigate the clinical experience with isavuconazole in Chinese individuals. PATIENTS/METHODS: Participants were Chinese healthy volunteers from a Phase I pharmacokinetics (PK) and safety study of single/multiple doses of isavuconazole (n = 36) and Chinese patients from the global Phase III SECURE study that assessed safety and efficacy of isavuconazole vs voriconazole for IFD treatment (n = 26). RESULTS: No clinically relevant differences in PK were found between Chinese and Western participants, although exposure was increased in Chinese volunteers. Treatment-emergent adverse events (TEAEs) were reported in 75.0% of healthy volunteers, many of which were infusion-related. No serious AEs were reported. In SECURE, findings in Chinese patients (n = 26) were similar to the global population. For patients who received ≥1 dose of study drug, allcause mortality from first dose to Day 42 was 10.0% (1/10) with isavuconazole and 25.0% (4/16) with voriconazole (treatment difference [95% confidence interval, CI]: -15.0% [-43.2%, 13.2%]). Overall response at the end of treatment for patients with proven/probable IFD was 25.0% and 16.7% with isavuconazole and voriconazole, respectively (treatment difference [95% CI] -8.3% [-60.2%, 43.5%]). Isavuconazole was associated with lower incidence of hepatobiliary, eye, skin, subcutaneous tissue and psychiatric disorders compared with voriconazole and lower incidence of treatment-related TEAEs, serious TEAES or death overall. CONCLUSIONS: Although further research is required, this study demonstrated a favourable risk-benefit profile of isavuconazole in Chinese patients.


Assuntos
Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Voluntários Saudáveis/estatística & dados numéricos , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Triazóis/farmacocinética , Triazóis/uso terapêutico , Administração Intravenosa , Administração Oral , Grupo com Ancestrais do Continente Asiático , China , Experimentação Humana , Humanos , Infecções Fúngicas Invasivas/etnologia , Nitrilas/efeitos adversos , Piridinas/efeitos adversos , Resultado do Tratamento , Triazóis/efeitos adversos
17.
Br J Haematol ; 193(2): 346-355, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33368155

RESUMO

Targeted therapy for chronic myeloid leukaemia (CML) has allowed for a near-normal patient life-expectancy; however, quality of life and aggravation of existing co-morbidities have posed new treatment challenges. In clinical practice, TKI dose reduction occurs frequently, often on multiple occasions, because of intolerance. We conducted a retrospective 'real-world practice' review of 246 patients receiving lower than standard dose (LD) TKI after the achievement of major molecular response (MR3), because of intolerable adverse events. In 274 of 298 cases of dose reduction (91·9%), MR3 was maintained at median follow-up of 27·3 months. One patient progressed to blast crisis while on LD TKI. Two patients developed two new ABL kinase domain mutations (T315I and V299L), of whom one had achieved deep molecular response on an alternative LD TKI at last follow-up. Seventy-six patients eventually discontinued LD TKI and the two-year treatment-free remission (TFR) rate in these patients was 74·1%. The majority of patients with CML in at least MR3 appear to be safely managed with LD TKI, although three of 246 patients had new events (progression and new mutation), indicating that this approach requires vigilance. TKI LD does not prevent the achievement of TFR in this patient population.


Assuntos
Redução da Medicação/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Indução de Remissão/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Compostos de Anilina/uso terapêutico , Comorbidade , Dasatinibe/administração & dosagem , Dasatinibe/efeitos adversos , Dasatinibe/uso terapêutico , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Mutação , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Qualidade de Vida , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Estudos Retrospectivos , Segurança , Resultado do Tratamento
19.
Fish Shellfish Immunol ; 107(Pt B): 427-434, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33186708

RESUMO

Chlorothalonil (CT) is a commonly used fungicide and its excessive application seriously threatens aquatic life and human health. Resveratrol (RSV) is a natural polyphenol and can be used as a therapeutic and preventive agent for the treatment of various diseases. To explore the toxic mechanism of CT exposure on fish kidney cell, as well as the alleviation effect of RSV, we established CT poisoning and/or RSV treatment fish kidney cell models. Ctenopharyngodon idellus kidney (CIK) cell line was treated with CT (5 µg/L) and/or RSV (10 µM) for 48 h. The results showed that CT exposure activated cytochromeP450s (CYPs) including CYP1A1, CYP1B1 and CYP1C, caused malondialdehyde (MDA) accumulation, inhibited glutathione (GSH) levels and glutathione peroxidase (GPX) activities, increased the expression of miR-15a and downregulated BCL2 and TNFα-induced protein 3 (TNFAIP3, A20), triggered mitochondrial pathway mediated apoptosis and receptor interacting serine/threonine kinase (RIP)-dependent necroptosis in CIK cells. However, cell death under CT exposure could be relieved by RSV treatment through inhibiting the expression of CYP1 family genes and restoring miR-15a/BCL2-A20 axis disorders. Overall, we conclude that RSV could relieve CT-induced apoptosis and necroptosis through miR-15a/Bcl2-A20 axis in CIK cells. These results enrich the toxicological mechanisms of the CT and confirm that RSV can be used as a potential antidote for CT poisoning.


Assuntos
Apoptose , Carpas/fisiologia , Fungicidas Industriais/efeitos adversos , Necroptose , Nitrilas/efeitos adversos , Substâncias Protetoras/farmacologia , Resveratrol/farmacologia , Animais , Linhagem Celular , Rim/efeitos dos fármacos , Rim/fisiologia , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais
20.
Arerugi ; 69(8): 669-677, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32963190

RESUMO

BACKGROUND: The causative chemicals responsible for nitrile rubber glove-induced allergic contact dermatitis have not been fully elucidated. SUBJECT: This case involved a 36-year-old female, who developed an erythematous rash on her hands after one and a half months of wearing nitrile rubber gloves at her workplace. METHODS: Patch tests were performed using the gloves as is, and the Japanese standard allergen 2008 and their components. The gloves were chemically analyzed and several detected substances were subjected to further patch testing. RESULTS: The patient exhibited positive patch test reactions to nitrile rubber gloves as is, as well as to the dithiocarbamate mix and thiuram mix in the Japanese standard allergen 2008. Further patch testing revealed positive reactions to zinc diethyldithiocarbamate (ZDEC) and tetraethylthiuram disulfide (TETD) and weak positive reactions to zinc dimethyldithiocarbamate (ZDMC) and tetramethylthiuram monosulfide (TMTM). Chemical analysis revealed that ethyl isothiocyanate (EITC) and butyl isothiocyanate (BITC), which might have been produced from dithiocarbamate-type accelerators (DTCs) or thiuram-type accelerators (thiurams) during the vulcanization process, were present in the nitrile rubber gloves the patient used at her workplace, as was ZDBC. No other DTCs or thiurams were detected. Patch testing of the detected materials produced positive reactions to EITC and BITC, but not to ZDBC. CONCLUSION: We diagnosed the patient with allergic contact dermatitis due to the EITC and BITC present in nitrile rubber gloves, and considered that alkyl isothiocyanate might also have played a causative role. We propose that nitrile rubber gloves should be produced without using vulcanization accelerators.


Assuntos
Dermatite Alérgica de Contato , Luvas Protetoras/efeitos adversos , Nitrilas/efeitos adversos , Adulto , Dermatite Alérgica de Contato/diagnóstico , Dermatite Alérgica de Contato/etiologia , Feminino , Humanos , Isotiocianatos/efeitos adversos , Testes do Emplastro
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