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2.
Molecules ; 26(4)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578679

RESUMO

This study aimed to discover concurrences of adverse drug reactions (ADRs) and derive models of the most frequent items of ADRs based on the SIDER database, which included 1430 marketed drugs and 5868 ADRs. First, common ADRs of organic drugs were manually reclassified according to side effects in the human system and followed by an association rule analysis, which found ADRs of digestive and nervous systems often occurred at the same time with a good association rule. Then, three algorithms, linear discriminant analysis (LDA), support vector machine (SVM) and deep learning, were used to derive models of ADRs of digestive and nervous systems based on 497 organic monomer drugs and to identify key structural features in defining these ADRs. The statistical results indicated that these kinds of QSAR models were good tools for screening ADRs of digestive and nervous systems, which gave the ROC AUC values of 81.5%, 98.9%, 91.5%, 69.5%, 78.4% and 78.8%, respectively. Then, these models were applied to investigate ADRs of 1536 organic compounds with four phase and zero rule-of-five (RO5) violations from the ChEMBL database. Based on the consensus ADRs' predictions of models, 58.1% and 42.6% of compounds were predicted to cause these two ADRs, respectively, indicating the significance of initial assessment of ADRs in early drug discovery.


Assuntos
Algoritmos , Simulação por Computador , Doenças do Sistema Digestório/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Doenças do Sistema Nervoso/induzido quimicamente , Preparações Farmacêuticas/química , Bases de Dados Factuais , Humanos
3.
Bull Cancer ; 108(3): 266-271, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33423777

RESUMO

INTRODUCTION: Taxanes are widely used in medical oncology. The aim of our study was to report and analyze the toxicity features of these drugs in Tunisian patients and to determine their impact on treatment response. METHODS: Our retrospective study concerned 90 patients treated by taxanes in a medical oncology unit, from January 2014 to January 2017. We collected their epidemiologic and anatomo-clinical data and we detailed toxicity features including types grades and impact on tumor response. RESULTS: Median age was 46 years. 80% of patients had breast cancer. Tumors were metastatic in 23.3% of cases. Nail toxicity was observed in 100% of patients. Grade I-II digestive toxicity was observed in 54.4% of cases. Hematological toxicity was noted in 42.2% of patients and it reached grade III-IV in five patients. Neurological toxicity occurred in 31% of patients and was grade III-IV in 6 cases. Alopecia was observed in 60% of patients. Fatigue was noted in 57.8% of patients. Myalgia was observed in 42.2% of patients. Toxicity did not affect the response to treatment. CONCLUSION: The taxanes' toxicity profile in Tunisian patients is characterized by more frequent digestive and nail toxicities and less frequent hematological toxicities, dose reduction and treatment delays than other populations.


Assuntos
Antineoplásicos/efeitos adversos , Taxoides/efeitos adversos , Adulto , Idoso , Alopecia/induzido quimicamente , Alopecia/epidemiologia , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Cisplatino/administração & dosagem , Doenças do Sistema Digestório/induzido quimicamente , Doenças do Sistema Digestório/epidemiologia , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Feminino , Fluoruracila/administração & dosagem , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças da Unha/induzido quimicamente , Doenças da Unha/epidemiologia , Doenças do Sistema Nervoso/induzido quimicamente , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias da Próstata/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Taxoides/administração & dosagem , Tunísia/epidemiologia
5.
Brain Nerve ; 73(1): 21-33, 2021 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-33361511

RESUMO

This article reviews the clinical features of toxicity in the peripheral and central nervous systems from anticancer drugs, including conventional cytotoxic chemotherapy, biologics, and targeted therapies, and excluding newer immunotherapies (immune checkpoint inhibitors and chimeric antigen receptor T cells). Neurologic complications from chemotherapy can be substantially disabling to patients and are being seen with increasing frequency because patients with cancer therapy are living longer and receiving multiple courses of anticancer regimens with combinations and longer duration. Clinicians, including neurologists, must know treatment-related neurotoxicity since discontinuation of the offending agent or dose adjustment may prevent further or permanent neurologic injury.


Assuntos
Antineoplásicos , Neoplasias , Doenças do Sistema Nervoso , Antineoplásicos/efeitos adversos , Humanos , Imunoterapia , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso/induzido quimicamente
6.
Medicine (Baltimore) ; 99(40): e22620, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019484

RESUMO

RATIONALE: Low-dose mitotane has been widely used for many decades in patients with advanced adrenocortical carcinoma (ACC), which exhibited good safety profiles compared with the high-dose regimen. The clinical efficacy and toxicity of mitotane are closely related to its plasma concentration, and therapeutic drug monitoring (TDM) is recommended. Until now, no severe adverse drug reaction (ADR) related to the toxic plasma level after a short-term treatment of low-dose mitotane has been published. PATIENT CONCERNS: A 50-year-old Chinese female presented with severe neurological adverse events related to a toxic plasma levels of 42.8 mg/L after 4 months treatment of low-dose mitotane. DIAGNOSES: During the course of therapy, no other medication could cause neurological adverse events. Therefore, we suspected a high sensitivity to the side effect of mitotane related to a toxic plasma level. INTERVENTIONS: Treatment of mitotane was stopped. OUTCOMES: The trough plasma concentration of mitotane decreased to 18.7 mg/mL after one and a half months, and the neurological symptoms gradually improved after drug discontinuance. LESSONS: The present case provides the first report of severe neurological adverse events induced by the short-term use of low-dose mitotane for adjuvant treatment in a patient with ACC, indicating that potentially severe ADR can also occur when using low-dose regimen in the early stage of treatment. TDM and early recognition could result in a favorable outcome.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/toxicidade , Mitotano/toxicidade , Doenças do Sistema Nervoso/induzido quimicamente , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/uso terapêutico , Grupo com Ancestrais do Continente Asiático/etnologia , Monitoramento de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Mitotano/sangue , Mitotano/uso terapêutico , Síndromes Neurotóxicas , Resultado do Tratamento , Suspensão de Tratamento
7.
Anesth Analg ; 131(5): 1616-1625, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33079886

RESUMO

BACKGROUND: Anesthesia in pregnant rodents causes neurotoxicity in fetal and offspring rodents. However, the underlying mechanisms and targeted treatments remain largely to be determined. Isoflurane and propofol are among commonly used anesthetics. Thus, we set out to investigate whether propofol can mitigate the isoflurane-induced neurotoxicity in mice. METHODS: Pregnant C57BL/6 mice at gestational day 15 (G15) were randomly assigned to 4 groups: control, isoflurane, propofol, and isoflurane plus propofol. Levels of interleukin (IL)-6 and poly-ADP ribose polymerase (PARP) fragment were measured in the brains of G15 embryos, and levels of postsynaptic density (PSD)-95 and synaptophysin were determined in the hippocampal tissues of postnatal day 31 (P31) offspring using Western blotting and immunohistochemical staining. Learning and memory functions in P31 offspring were determined using a Morris water maze test. RESULTS: Isoflurane anesthesia in pregnant mice at G15 significantly increased brain IL-6 (222.6% ± 36.45% vs 100.5% ± 3.43%, P < .0001) and PARP fragment (384.2% ± 50.87% vs 99.59% ± 3.25%, P < .0001) levels in fetal mice and reduced brain PSD-95 (30.76% ± 2.03% vs 100.8% ± 2.25%, P < .0001) and synaptophysin levels in cornu ammonis (CA) 1 region (57.08% ± 4.90% vs 100.6% ± 2.20%, P < .0001) and dentate gyrus (DG; 56.47% ± 3.76% vs 99.76% ± 1.09%, P < .0001) in P31 offspring. Isoflurane anesthesia also impaired cognitive function in offspring at P31. Propofol significantly mitigated isoflurane-induced increases in brain IL-6 (117.5% ± 10.37% vs 222.6% ± 36.45%, P < .0001) and PARP fragment (205.1% ± 35.99% vs 384.2% ± 50.87%, P < .0001) levels in fetal mice, as well as reductions in PSD-95 (49.79% ± 3.43% vs 30.76% ± 2.03%, P < .0001) and synaptophysin levels in CA1 region (85.57% ± 2.97% vs 57.08% ± 4.90%, P < .0001) and DG (85.05% ± 1.87% vs 56.47% ± 3.76%, P < .0001) in hippocampus of P31 offspring. Finally, propofol attenuated isoflurane-induced cognitive impairment in offspring. CONCLUSIONS: These findings suggest that gestational isoflurane exposure in mice induces neuroinflammation and apoptosis in embryos and causes cognitive impairment in offspring. Propofol can attenuate these isoflurane-induced detrimental effects.


Assuntos
Anestésicos Inalatórios/toxicidade , Anestésicos Intravenosos/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Isoflurano/antagonistas & inibidores , Isoflurano/toxicidade , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/prevenção & controle , Propofol/farmacologia , Animais , Animais Recém-Nascidos , Química Encefálica/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Disfunção Cognitiva/psicologia , Proteína 4 Homóloga a Disks-Large/metabolismo , Feminino , Feto , Interleucina-6/metabolismo , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Poli(ADP-Ribose) Polimerase-1/metabolismo , Gravidez , Sinaptofisina/metabolismo
9.
Arch. argent. pediatr ; 118(5): e480-e485, oct 2020. ilus, tab
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1122533

RESUMO

Se presentan dos pacientes que desarrollaron deterioro visual debido a una intoxicación por monóxido de carbono. Ellos fueron tratados con oxígeno hiperbárico y recuperaron no solo su visión, sino que, además, mejoraron su signo-sintomatología neurológica. Se cree que la implementación de oxígeno hiperbárico, incluso en un período tardío, será efectiva para revertir las secuelas neurológicas.


We present two patients who developed visual deterioration due to carbon monoxide poisoning. They were treated with hyperbaric oxygen and recovered not only their vision but also they improved neurological signs and symptoms. We believe that implementation of hyperbaric oxygen, even in a late period of time will be effective in reversing neurological sequela


Assuntos
Humanos , Masculino , Criança , Adolescente , Intoxicação por Monóxido de Carbono/complicações , Cegueira/induzido quimicamente , Oxigenação Hiperbárica , Doenças do Sistema Nervoso/induzido quimicamente
10.
Neurol Neurochir Pol ; 54(5): 399-409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32955099

RESUMO

Gadolinium-based contrast agents (GBCAs) are widely used in magnetic resonance imaging (MRI) to help with the diagnostic and monitoring processes of many diseases, including neurological disorders. Initially, it was assumed that GBCAs carry minimal risk, are safe and well tolerated. But recent reports of GBCA-associated deposition in many body tissues have raised concerns about the broader health impacts of gadolinium exposure. The aim of this review was to summarise knowledge regarding gadolinium deposition, primarily in the brain structures, and of potential GBCA-associated toxicity. Moreover, we discuss the current recommendations on the use of GBCAs, as well as alternative contrast agents and imaging techniques.


Assuntos
Doenças do Sistema Nervoso , Encéfalo , Meios de Contraste/efeitos adversos , Gadolínio , Humanos , Imagem por Ressonância Magnética , Doenças do Sistema Nervoso/induzido quimicamente
11.
Rev Environ Health ; 35(3): 265-269, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32712592

RESUMO

Objectives This research aims to analyse the relationship between urine mercury levels and neurological problems. Methods This research is an observational study with a cross-sectional approach. There are 44 goldsmiths in the gold jewellery small scale industry involved in this study. Urine mercury levels were measured using an atomic absorption spectrophotometer. Neurological problems were assessed by a medician. Data collected includes age, time of exposure, work duration, smoking behaviour and nutrition status of the goldsmiths which were obtained by interview. Results The results showed that the concentration of mercury in the goldsmith's urine was around 0.93-64.59 µg/L. The analysis showed that there were 63% of goldsmiths experiencing neurological problems, such as tremors (9.1%) and knee pass reflex (6.8%). The bivariate analysis showed that there is no significant relationship between the concentration of mercury (p=0.133), age (p=0.155), time of exposure (p=0.702), time of working (p=0.354), smoking behaviour (p=0.169) and nutrition status (p=0.541) with neurological problems. Conclusions The goldsmiths who had high levels of mercury in urine samples were diagnosed with at least one of the neurological symptoms. It is recommended that the goldsmith use personal protective equipment during work such as mask, glasses and gloves.


Assuntos
Mercúrio/efeitos adversos , Doenças do Sistema Nervoso/epidemiologia , Exposição Ocupacional/efeitos adversos , Estudos Transversais , Monitoramento Ambiental , Ouro , Indonésia/epidemiologia , Mineração , Doenças do Sistema Nervoso/induzido quimicamente
12.
Artigo em Inglês | MEDLINE | ID: mdl-32645824

RESUMO

Environmental lead (Pb) exposure is closely associated with pathogenesis of a range of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), attention deficit/hyperactivity disorder (ADHD), etc. Epigenetic machinery modulates neural development and activities, while faulty epigenetic regulation contributes to the diverse forms of CNS (central nervous system) abnormalities and diseases. As a potent epigenetic modifier, lead is thought to cause neurological disorders through modulating epigenetic mechanisms. Specifically, increasing evidence linked aberrant DNA methylations, histone modifications as well as ncRNAs (non-coding RNAs) with AD cases, among which circRNA (circular RNA) stands out as a new and promising field for association studies. In 23-year-old primates with developmental lead treatment, Zawia group discovered a variety of epigenetic changes relating to AD pathogenesis. This is a direct evidence implicating epigenetic basis in lead-induced AD animals with an entire lifespan. Additionally, some epigenetic molecules associated with AD etiology were also known to respond to chronic lead exposure in comparable disease models, indicating potentially interlaced mechanisms with respect to the studied neurotoxic and pathological events. Of note, epigenetic molecules acted via globally or selectively influencing the expression of disease-related genes. Compared to AD, the association of lead exposure with other neurological disorders were primarily supported by epidemiological survey, with fewer reports connecting epigenetic regulators with lead-induced pathogenesis. Some pharmaceuticals, such as HDAC (histone deacetylase) inhibitors and DNA methylation inhibitors, were developed to deal with CNS disease by targeting epigenetic components. Still, understandings are insufficient regarding the cause-consequence relations of epigenetic factors and neurological illness. Therefore, clear evidence should be provided in future investigations to address detailed roles of novel epigenetic factors in lead-induced neurological disorders, and efforts of developing specific epigenetic therapeutics should be appraised.


Assuntos
Doença de Alzheimer , DNA/genética , Chumbo/efeitos adversos , Doenças do Sistema Nervoso/induzido quimicamente , Animais , Metilação de DNA/efeitos dos fármacos , Epigênese Genética , Inibidores de Histona Desacetilases , Doenças do Sistema Nervoso/genética , Doenças Neurodegenerativas/genética
13.
Environ Health ; 19(1): 84, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698901

RESUMO

BACKGROUND: Previous biomonitoring studies have shown that people in the rural population of Coquimbo, the major agricultural area in northern Chile are being occupationally and environmentally exposed to organophosphate/carbamate (OP/CB) pesticides. Given their harmful effects, this study had two aims; first, to evaluate the effect of cumulative or chronic exposure to OP/CB pesticides on the neurobehavioral performance of agricultural workers and rural inhabitants; second, to determine if changes in the neurobehavioral performance are associated to changes in blood biomarkers of OP/CB pesticides during the spray season, when exposure is higher. METHODS: For the first aim, a cross sectional study of neurobehavioral performance in adult volunteers (men and women, 18-50 years-old, right-handed) was carried out in the pre-spray season. Sampling was done by convenience and a questionnaire was used to categorize participants depending on their level of chronic exposure, as either: occupationally exposed (OE, n = 87), environmentally exposed (EE, n = 81), or non-exposed controls or reference group (RG, n = 100). A neurobehavioral test battery consisting of 21 tests to measure cognitive, motor and emotional state was applied. For the second aim, neurobehavioral measures were taken a second time from EE and OE groups during the spray season, and their exposure corroborated by blood-based biomarker inhibition. RESULTS: Lower neurobehavioral performance was observed in the pre-spray evaluation of EE and OE groups compared to the non-exposed, OE being the worst performing group. Seasonal exposure impaired performance in both exposure groups on all tests except those on attention and mood. Data modeling of the basal (pre-spray) measurements showed that the level of exposure was the best predictor of performance. During spraying, inhibition of BChE activity in the EE group was the best predictor of low performance in tests measuring logical, auditory and visual memory, inhibitory control of cognitive interference, constructional and planning abilities, executive functions, and motor speed and coordination. CONCLUSION: Long-term occupational or environmental exposure to pesticides caused impairment in neurobehavioral functioning, which worsened during the spraying season, mainly in EE. BChE inhibition was the best predictor for seasonal neurobehavioral changes in EE.


Assuntos
Doenças dos Trabalhadores Agrícolas/induzido quimicamente , Exposição Ambiental/efeitos adversos , Fazendeiros/estatística & dados numéricos , Doenças do Sistema Nervoso/induzido quimicamente , Praguicidas/efeitos adversos , População Rural/estatística & dados numéricos , Adulto , Biomarcadores/sangue , Carbamatos/efeitos adversos , Chile , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Exposição Ocupacional/efeitos adversos , Organofosfatos/efeitos adversos , Adulto Jovem
14.
Sci Rep ; 10(1): 9483, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528183

RESUMO

Chronic kidney disease (CKD) is deemed to be a worldwide health concern connected with neurological manifestations. The etiology of central nervous system (CNS) disorders in CKD is still not fully understood, however particular attention is currently being paid to the impact of accumulated toxins. Indoxyl sulfate (IS) is one of the most potent uremic toxins. The purpose of the present study was to assess IS concentrations in the cerebellum, brainstem, cortex, hypothalamus, and striatum with hippocampus of rats chronically exposed to IS. To evaluate IS impact on neurochemical and behavioral alterations, we examined its influence on brain levels of norepinephrine, epinephrine, dopamine, serotonin and their metabolites, as well as changes in behavioral tests (open field test, elevated plus maze test, chimney test, T maze test, and splash test). Our results show the highest IS accumulation in the brainstem. IS leads to behavioral alterations involving apathetic behavior, increased stress sensitivity, and reduced locomotor and exploratory activity. Besides, IS contributes to the impairment of spatial memory and motor coordination. Furthermore, we observed reduced levels of norepinephrine, dopamine or serotonin, mainly in the brainstem. Our findings indicate that IS can be one of the crucial uremic factors responsible for altered mental status in CKD.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Indicã/farmacologia , Toxinas Biológicas/toxicidade , Uremia/induzido quimicamente , Animais , Sistema Nervoso Central/metabolismo , Dopamina/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Modelos Animais , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/metabolismo , Norepinefrina/metabolismo , Ratos , Ratos Wistar , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/metabolismo , Serotonina/metabolismo , Memória Espacial/efeitos dos fármacos , Uremia/metabolismo
15.
Rev Environ Health ; 35(3): 245-256, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32598325

RESUMO

Background Epidemiological studies have historically focused on single toxicants, or toxic chemicals, and neurodevelopment, even though the interactions of chemicals and nutrients may result in additive, synergistic, antagonistic, or potentiating effects on neurological endpoints. Investigating the impact of environmentally-relevant chemical mixtures, including heavy metals and endocrine disrupting chemicals (EDCs), is more reflective of human exposures and may result in more refined environmental policies to protect the public. Objective In this review, we provide a summary of epidemiological studies that have analyzed chemical mixtures of heavy metals and EDCs and neurobehavior utilizing multi-chemical models, including frequentist and Bayesian methods. Content Studies investigating chemicals and neurobehavior have the opportunity to not only examine the impact of chemical mixtures, but they can also identify chemicals from a mixture that may play a key role in neurotoxicity, investigate interactive effects, estimate non-linear dose response, and identify potential windows of susceptibility. The examination of neurobehavioral domains is particularly challenging given that traits emerge and change over time and subclinical nuances of neurobehavior are often unrecognized. To date, only a handful of epidemiological studies examining neurodevelopment have utilized multi-pollutant models in the investigation of heavy metals and EDCs. However, these studies were successful in identifying contaminants of importance from the exposure mixtures. Summary and Outlook Investigators are encouraged to broaden their focus to include more environmentally relevant mixtures of chemicals using advanced statistical approaches, particularly to aid in identifying potential mechanisms underlying associations.


Assuntos
Disruptores Endócrinos/efeitos adversos , Exposição Ambiental/efeitos adversos , Poluentes Ambientais/efeitos adversos , Metais Pesados/efeitos adversos , Doenças do Sistema Nervoso/epidemiologia , Animais , Humanos , Camundongos , Doenças do Sistema Nervoso/induzido quimicamente , Ratos
16.
JAMA Netw Open ; 3(4): e202072, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32250433

RESUMO

Importance: Chimeric antigen receptor (CAR) T-cell therapies are currently administered at a limited number of cancer centers and are primarily delivered in an inpatient setting. However, variations in total costs associated with these therapies remain unknown. Objective: To estimate the economic differences in the administration of CAR T-cell therapy by the site of care and the incidence of key adverse events. Design, Setting, and Participants: A decision-tree model was designed to capture clinical outcomes and associated costs during a predefined period (from lymphodepletion to 30 days after the receipt of CAR T-cell infusion) to account for the potential incidence of acute adverse events and to evaluate variations in total costs for the administration of CAR T-cell therapy by site of care. Cost estimates were from the health care practitioner perspective and were based on data obtained from the literature and publicly available databases, including the Healthcare Cost and Utilization Project National Inpatient Sample, the Medicare Hospital Outpatient Prospective Payment System, the Medicare physician fee schedule, the Centers for Medicare and Medicaid Services Healthcare Common Procedure Coding System, and the IBM Micromedex RED BOOK. The model evaluated an average adult patient with relapsed or refractory large B-cell lymphoma who received CAR T-cell therapy in an academic inpatient hospital or nonacademic specialty oncology network. Intervention: The administration of CAR T-cell therapy. Main Outcomes and Measures: Total cost of the administration of CAR T-cell therapy by site of care. The costs associated with lymphodepletion, acquisition and infusion of CAR T cells, and management of acute adverse events were also examined. Results: The estimated total cost of care associated with the administration of CAR T-cell therapy was $454 611 (95% CI, $452 466-$458 267) in the academic hospital inpatient setting compared with $421 624 (95% CI, $417 204-$422 325) in the nonacademic specialty oncology network setting, for a difference of $32 987. After excluding the CAR T-cell acquisition cost, hospitalization and office visit costs were $53 360 (65.3% of the total cost) in academic inpatient hospitals and $23 526 (48.4% of the total cost) in nonacademic specialty oncology networks. The administration of CAR T-cell therapy in nonacademic specialty oncology networks was associated with a $29 834 (55.9%) decrease in hospitalization and office visit costs and a $3154 (20.1%) decrease in procedure costs. Conclusions and Relevance: The potential availability of CAR T-cell therapies that are associated with a lower incidence of adverse events and are suitable for outpatient administration may reduce the total costs of care by enabling the use of these therapies in nonacademic specialty oncology networks.


Assuntos
Análise Custo-Benefício/métodos , Custos de Cuidados de Saúde/estatística & dados numéricos , Imunoterapia Adotiva/economia , Linfoma de Células B/tratamento farmacológico , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adulto , Assistência Ambulatorial/economia , Síndrome da Liberação de Citocina/epidemiologia , Gerenciamento de Dados , Hospitalização/economia , Humanos , Imunoterapia Adotiva/efeitos adversos , Infusões Intravenosas/métodos , Pacientes Internados , Medicare/economia , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/epidemiologia , Recidiva , Estados Unidos/epidemiologia
17.
Malar J ; 19(1): 111, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32169086

RESUMO

BACKGROUND: Tafenoquine is an 8-aminoquinoline anti-malarial drug recently approved as a single-dose (300 mg) therapy for Plasmodium vivax relapse prevention, when co-administered with 3-days of chloroquine or other blood schizonticide. Tafenoquine 200 mg weekly after a loading dose is also approved as travellers' prophylaxis. The development of tafenoquine has been conducted over many years, using various dosing regimens in diverse populations. METHODS: This review brings together all the preclinical and clinical data concerning tafenoquine central nervous system safety. Data were assembled from published sources. The risk of neuropsychiatric adverse events (NPAEs) with single-dose tafenoquine (300 mg) in combination with chloroquine to achieve P. vivax relapse prevention is particularly examined. RESULTS: There was no evidence of neurotoxicity with tafenoquine in preclinical animal models. In clinical studies in P. vivax relapse prevention, nervous system adverse events, mainly headache and dizziness, occurred in 11.4% (36/317) of patients with tafenoquine (300 mg)/chloroquine versus 10.2% (19/187) with placebo/chloroquine; and in 15.5% (75/483) of patients with tafenoquine/chloroquine versus 13.3% (35/264) with primaquine (15 mg/day for 14 days)/chloroquine. Psychiatric adverse events, mainly insomnia, occurred in 3.8% (12/317) of patients with tafenoquine/chloroquine versus 2.7% (5/187) with placebo/chloroquine; and in 2.9% (14/483) of patients with tafenoquine/chloroquine versus 3.4% (9/264) for primaquine/chloroquine. There were no serious or severe NPAEs observed with tafenoquine (300 mg)/chloroquine in these studies. CONCLUSIONS: The risk:benefit of single-dose tafenoquine/chloroquine in P. vivax relapse prevention is favourable in the presence of malaria, with a low risk of NPAEs, similar to that seen with chloroquine alone or primaquine/chloroquine.


Assuntos
Aminoquinolinas/uso terapêutico , Malária Vivax/tratamento farmacológico , Doenças do Sistema Nervoso/induzido quimicamente , Prevenção Secundária/métodos , Aminoquinolinas/efeitos adversos , Antimaláricos , Humanos , Plasmodium vivax/efeitos dos fármacos
18.
Life Sci ; 249: 117538, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32169521

RESUMO

Inflammaging is known as an imbalance between pro-inflammatory and anti-inflammatory immune mechanisms, being related to the onset of neurological disorders, such as major depression and Alzheimer's disease. Considering the known disadvantages regarding the FDA approved drug to manage such illnesses, resveratrol emerges as a natural drug candidate, despite its low bioavailability. In this study, resveratrol analogues were evaluated for their capacity of inhibiting acetylcholinesterase in silico, in vitro, and in vivo. Molecular docking simulations pointed out RSVA1 and RSVA6 as potent inhibitors, even more than resveratrol. Ellman's assay demonstrated RSVA6 as capable of inhibiting 92.4% of the enzyme activity. Further, male Swiss mice were pretreated with RSVA6 (100 mg kg-1) 60 min before receiving scopolamine (1 mg kg-1). The Novel Recognition Object (NOR), Object Location (OLT), and Buried Pellet tests (BPL) demonstrated an RSVA6 neuroprotective effect. In the second round of tests, mice received a single intraperitoneal injection of lipopolysaccharide (0.5 mg kg-1) 24 h before treatment with RSVA6 (1, 10, and 100 mg kg-1). The Open Field (OFT), Tail Suspension (TST), and Splash tests (ST) were evaluated. LPS had no significant effect on the crossing and rearing number, indicating an association between the immobility time and anhedonia observed in the TST and ST, respectively, with depressive-like behavior. RSVA6 significantly reduced the depressive-like behavior triggered by LPS in the TST and ST. Altogether, our data suggest RSVA6 as a potential drug candidate for the treatment of neuroinflammatory conditions.


Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Resveratrol/uso terapêutico , Animais , Simulação por Computador , Técnicas In Vitro , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Simulação de Acoplamento Molecular , Doenças do Sistema Nervoso/induzido quimicamente , Resveratrol/análogos & derivados , Escopolamina/administração & dosagem
19.
Ann Rheum Dis ; 79(5): 566-572, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32161058

RESUMO

OBJECTIVES: To investigate whether tumour necrosis factor alpha inhibitors (TNFis) are associated with an increased risk of neuroinflammatory diseases among patients with arthritic diseases. METHODS: Cohorts of patients with rheumatoid arthritis (RA, n=25 796), psoriatic arthritis (PsA, n=8586) and ankylosing spondylitis (AS, n=9527) who initiated a TNFi treatment year 2000-2017 were identified from nationwide clinical rheumatology registers in Sweden and Denmark. Information on demyelinating disease and inflammatory neuropathy diagnoses was retrieved from prospective linkage to National Patients Register. A Cox proportional hazard model was used to estimate HRs and 95% CI comparing TNFi exposed and non-exposed, by disease and country. RESULTS: Among 111 455 patients with RA, we identified 270 (Sweden) and 51 (Denmark) events (all types of neuroinflammatory diseases combined), corresponding to crude incidence rates (per 1000 person-years) of 0.37 (Sweden) and 0.39 (Denmark) in TNFi-treated patients vs 0.39 (Sweden) and 0.28 (Denmark) in unexposed patients, and an age-sex-calendar-period-adjusted HR (95% CI) of 0.97 (0.72 to 1.33) (Sweden) and 1.45 (0.74 to 2.81) (Denmark) in TNFi exposed compared with non-exposed patients. For a total of 64 065 AS/PsA patients, the corresponding numbers were: 196 and 32 events, crude incidence rates of 0.59 and 0.87 in TNFi-treated patients vs 0.40 and 0.19 in unexposed patients, and HRs of 1.50 (1.07 to 2.11) and 3.41 (1.30 to 8.96), for Sweden and Denmark, respectively. For multiple sclerosis, the patterns of HRs were similar. CONCLUSIONS: Use of TNFi in AS/PsA, but not in RA, was associated with increased risk of incident neuroinflammatory disease, though the absolute risk was below one in 1000 patients/year.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Doenças Desmielinizantes/induzido quimicamente , Sistema de Registros , Espondilite Anquilosante/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Idoso , Artrite Psoriásica/diagnóstico , Artrite Reumatoide/diagnóstico , Estudos de Coortes , Doenças Desmielinizantes/epidemiologia , Dinamarca , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Espondilite Anquilosante/diagnóstico , Suécia , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Fator de Necrose Tumoral alfa/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores
20.
Ann Hematol ; 99(4): 835-838, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32076826

RESUMO

Despite improvement in survival of newly diagnosed adult precursor B-acute lymphoblastic leukemia/lymphoma (B-ALL), the results of relapsed/refractory disease are poor. Blinatumomab, a bispecific monoclonal antibody directed against CD19/CD3 show clinical activity against relapsed/refractory B-ALL and in minimal residual disease (MRD)-positive patients.We report our "real-world" experience with blinatumomab in patients with relapsed/refractory B-ALL.Twenty-one patients, at a median age 52 years with median disease duration of 10 months, were included. Indications for treatment were hematological relapse (n = 17), MRD positivity (n = 2), inability to continue intensive chemotherapy (n = 1), and bridging to a second alloSCT (n = 1). Blinatumomab was given as first salvage in 11 patients and after at least one prior salvage treatment in eight.Complete response (CR) was newly achieved in 47% and was maintained in 75% of patients with baseline CR. At a median follow-up of 12.4 months, 13 patients were alive, and 11 in CR. Median leukemia-free survival was 8.7 months, and median overall survival was 15.2 months. Median leukemia-free survival and overall survival were not reached in patients proceeding to alloSCT compared to 5.1 and 15.2 months, respectively, for patients who did not receive stem cell transplantation.Treatment was well tolerated with neurological events reported in two patients (10%) and GI events in three patients (14%). Cytokine storm was reported in four patients (19%).In conclusion, treatment with blinatumomab is effective and tolerable in adult patients with relapsed/refractory B-ALL outside of a clinical trial stetting.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Complexo CD3/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Biespecíficos/efeitos adversos , Especificidade de Anticorpos , Antineoplásicos Imunológicos/efeitos adversos , Terapia Combinada , Citocinas/metabolismo , Intervalo Livre de Doença , Feminino , Gastroenteropatias/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Doenças do Sistema Nervoso/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Recidiva , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
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