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1.
Int J Hematol ; 110(6): 665-674, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31473943

RESUMO

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations in patients with acute myeloid leukemia (AML) are associated with early relapse and poor survival. This multicenter, single-arm, two-stage phase 2 study (NCT02984995) was conducted to evaluate the efficacy and safety of quizartinib hydrochloride (initial dose 20/30 mg/day), an oral, highly potent, selective FLT3 inhibitor in Japanese patients (median age 65 years) with FLT3-ITD positive relapsed/refractory (R/R) AML. The composite complete remission (CRc) rate (primary endpoint) was 53.8% (90% confidence interval 36.2-70.8%) for evaluable patients in the efficacy analysis set. The median duration of CRc and overall survival was 16.1 weeks and 34.1 weeks, respectively. The most frequent treatment-emergent adverse events (TEAEs) were febrile neutropenia (43.2%), platelet count decreased (37.8%), and QT prolonged (35.1%). Two (5.4%) patients experienced TEAEs associated with treatment discontinuation. All serious TEAEs (45.9%), except febrile neutropenia (16.2%), were reported in ≤ 2 patients. The incidence of QTcF 451-480 ms and 481-500 ms was 37.8% and 2.7%, respectively. No QTcF > 500 ms, events of torsade de pointes or arrhythmia with clinical symptoms were reported. Quizartinib monotherapy was well tolerated and resulted in clinically meaningful reductions in blast count in Japanese patients with FLT3-ITD R/R AML.


Assuntos
Benzotiazóis/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Terapia de Salvação/métodos , Tirosina Quinase 3 Semelhante a fms/genética , Idoso , Benzotiazóis/efeitos adversos , Benzotiazóis/uso terapêutico , Feminino , Humanos , Japão , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Indução de Remissão/métodos , Terapia de Salvação/efeitos adversos , Terapia de Salvação/mortalidade , Resultado do Tratamento
2.
Cancer Chemother Pharmacol ; 84(4): 799-807, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31385001

RESUMO

PURPOSE: Quizartinib, a potent, selective FMS-like tyrosine kinase 3 (FLT3) inhibitor, is currently in phase 3 development for patients with FLT3-internal tandem duplication-mutated acute myeloid leukemia (AML). Acid-reducing agents (ARAs; e.g., proton pump inhibitors) are frequently used during AML treatment. Since quizartinib demonstrates pH-dependent solubility, the effect of lansoprazole coadministration on pharmacokinetics (PK) of quizartinib tablet formulation was assessed. METHODS: An open-label, parallel-group study randomized 64 healthy adults to single-dose quizartinib 30 mg alone (reference) or lansoprazole (60 mg once daily, days 1-5) + single-dose quizartinib 30 mg (day 5) (test). Plasma concentrations of quizartinib and its active metabolite, AC886, were measured to 504 h postdose; the effect of lansoprazole on quizartinib PK was assessed by analysis of variance. RESULTS: Quizartinib geometric mean ratios (test/reference) and 90% confidence intervals for maximum observed plasma concentration (Cmax), area under the concentration-time curve to last measurable drug concentration (AUClast), and AUC to infinity were 86.11% (78.4%, 94.6%), 93.96% (79.6%, 110.9%), and 95.30% (80.2%, 113.3%), respectively. Comparisons showed a modest decrease in quizartinib absorption when co-administered with lansoprazole, with lower limits for Cmax and AUClast just below 80-125% limits. Treatment-emergent adverse events were mild or moderate; the most frequent in either treatment group were headache [quizartinib alone: (n = 3) 10%], upper respiratory tract infection [quizartinib alone: (n = 2) 6.7%; lansoprazole + quizartinib: (n = 3) 9.1%], and muscle tightness [quizartinib alone: (n = 2) 6.7%]. CONCLUSIONS: Concomitant lansoprazole had minimal effect on quizartinib PK as a formulated tablet, indicating that quizartinib can be administered with ARAs.


Assuntos
Benzotiazóis , Lansoprazol , Compostos de Fenilureia , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzotiazóis/administração & dosagem , Benzotiazóis/efeitos adversos , Benzotiazóis/farmacocinética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Lansoprazol/administração & dosagem , Lansoprazol/efeitos adversos , Lansoprazol/farmacocinética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/farmacocinética , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
3.
Int J Hematol ; 110(6): 654-664, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31359361

RESUMO

Expanded therapeutic options are warranted for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations. The present phase 1, multicenter, open-label, dose-escalation and dose-expansion study was conducted to assess the safety, pharmacokinetics, and efficacy of multiple-dose monotherapy of the FLT3 inhibitor, quizartinib, in Japanese patients with R/R AML. Patients received oral quizartinib, once daily, under fasting conditions in 28-day cycles. Sixteen patients (median age, 68.0 years; male, 56.3%; FLT3-ITD positive, 43.8%) received quizartinib (9, 3, and 4 patients at 20, 30, and 60 mg/day, respectively; median treatment duration, 95.0 days; median relative dose intensity, 100.0%). No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were electrocardiogram QT prolonged (43.8%, grade 1 or 2) followed by nausea and pyrexia (37.5% each). No quizartinib-related deaths were reported. A dose-dependent increase of quizartinib and its active metabolite AC886 levels was observed at the steady state. The composite complete remission rate was 37.5%. Quizartinib was well tolerated in Japanese R/R AML patients at doses up to 60 mg/day; quizartinib 60 mg/day was considered as the recommended dose for the Japanese patient population in a subsequent study.Trial registration ClinicalTrials.gov identifier NCT02675478.


Assuntos
Benzotiazóis/farmacocinética , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/farmacocinética , Idoso , Benzotiazóis/administração & dosagem , Benzotiazóis/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Japão , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases , Terapia de Salvação/efeitos adversos , Terapia de Salvação/métodos , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
4.
Contact Dermatitis ; 81(4): 262-265, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31006870

RESUMO

BACKGROUND: Allergic contact dermatitis caused by leather is common, and several responsible allergens, such as tanning agents, glues, mercaptobenzothiazole derivatives, and dyes, but also antimicrobials and antifungals, are involved. MATERIAL AND METHODS: Three female patients were referred to the Departments of Dermatology in a Belgian university hospital following skin reactions caused by leather products (shoes, belt, and car seats). They were patch tested with the European baseline series and samples of suspected leather products, and additionally with 2-(thiocyanomethylthio)benzothiazole (TCMTB), an antifungal agent previously reported to be a contact allergen in footwear. Chromatographic analyses of samples of all the leather materials tested were performed at the Department of Occupational and Environmental Dermatology in Malmö, Sweden. RESULTS: The patients reacting to the leather samples were shown to be sensitized to TCMTB, the presence of which could be confirmed by chemical analyses of samples obtained from the patients. CONCLUSION: Patch tests with TCMTB should be considered in patients with contact dermatitis caused by leather items.


Assuntos
Antifúngicos/efeitos adversos , Benzotiazóis/efeitos adversos , Dermatite Alérgica de Contato/etiologia , Dermatoses do Pé/induzido quimicamente , Dermatoses da Perna/induzido quimicamente , Tiocianatos/efeitos adversos , Adolescente , Adulto , Automóveis , Dermatite Alérgica de Contato/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Testes do Emplastro , Sapatos
5.
J Pharmacol Exp Ther ; 369(2): 188-199, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30819762

RESUMO

The anabolic effects of ß 2-adrenoceptor (ß 2-AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of ß 2-AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived ß 2-AR agonist in comparison with formoterol as a representative ß 2-AR agonist that have been well characterized. In vitro, 5-HOB has nanomolar affinity for the human ß 2-AR and selectivity over the ß 1-AR and ß 3-AR. 5-HOB also shows potent agonistic activity at the ß 2-AR in primary skeletal muscle myotubes and induces hypertrophy of skeletal muscle myotubes. Compared with formoterol, 5-HOB demonstrates comparable full-agonist activity on cAMP production in skeletal muscle cells and skeletal muscle tissue-derived membranes. In contrast, a greatly reduced intrinsic activity was determined in cardiomyocytes and cell membranes prepared from the rat heart. In addition, 5-HOB shows weak effects on chronotropy, inotropy, and vascular relaxation compared with formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats with attenuated effects on heart weight and ejection fraction, unlike formoterol. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB compared with formoterol. In conclusion, the pharmacological profile of 5-HOB indicates superior tissue selectivity compared with the conventional ß 2-AR agonist formoterol in preclinical studies and supports the notion that such tissue-selective agonists should be investigated for the safe treatment of muscle-wasting conditions without cardiovascular limiting effects.


Assuntos
Benzotiazóis/química , Benzotiazóis/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Segurança , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Anabolizantes/efeitos adversos , Anabolizantes/química , Anabolizantes/farmacologia , Anabolizantes/uso terapêutico , Animais , Benzotiazóis/efeitos adversos , Benzotiazóis/uso terapêutico , Células CHO , Cricetulus , Coração/efeitos dos fármacos , Humanos , Hipertrofia/tratamento farmacológico , Cinética , Macaca mulatta , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miócitos Cardíacos/efeitos dos fármacos , Ratos
6.
Medicine (Baltimore) ; 97(34): e11316, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30142750

RESUMO

BACKGROUND: In order to increase treatment choices for patients with Parkinson disease (PD), we performed a retrospective assessment of adverse events associated with a novel once-daily extended-release (ER) formulation versus the standard immediate-release (IR) of the nonergolinic dopamine agonist, pramipexole. METHODS: The PubMed and Embase databases, as well as the foreign language medical information resource retrieval platform were searched from 2007 to 2017. The relative risks (RR) of various adverse events with 95% confidence intervals (95% CIs) were generated. The Modified Jadad score (MJs) was used to assess the quality of individual studies. Funnel plots were used to evaluate publication bias. RESULTS: Three randomized controlled trials involving 1021 patients were included in this meta-analysis. We evaluated common adverse events associated with pramipexole in the gastrointestinal and nervous systems. These included the typical gastrointestinal symptom of nausea (RR = 0.96, 95% CI: 0.72-1.28; P = .80 > .05) and nervous system symptoms of somnolence (RR = 1.16, 95% CI: 0.95-1.43; P = .14 > .05), dizziness (RR = 1.11, 95% CI: 0.80-1.54; P = .54 > .05), and dyskinesia (RR = 0.87, 95% CI: 0.47-1.60; P = .66 > .05). CONCLUSION: Patients with PD treated with 2 different pramipexole formulations (ER and IR) had similar incidences of common adverse events.


Assuntos
Benzotiazóis/efeitos adversos , Agonistas de Dopamina/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Benzotiazóis/uso terapêutico , Preparações de Ação Retardada/efeitos adversos , Agonistas de Dopamina/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Masculino , Pramipexol , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Índice de Gravidade de Doença
7.
BMC Cancer ; 18(1): 790, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30081867

RESUMO

BACKGROUND: Quizartinib, an inhibitor of class III receptor tyrosine kinases (RTKs), is currently in phase 3 development for the treatment of acute myeloid leukemia (AML) bearing internal tandem duplications in the FLT3 gene. Aberrant RTK signaling is implicated in the pathogenesis of a variety of solid tumors, suggesting that inhibiting quizartinib-sensitive RTKs may be beneficial in precision cancer therapy. METHODS: This was a phase 1, open-label, modified Fibonacci dose-escalation study of orally administered quizartinib in patients with advanced solid tumors whose disease progressed despite standard therapy or for which there was no available standard treatment. Patients received quizartinib dihydrochloride (henceforth referred to as quizartinib) once daily throughout a 28-day treatment cycle. The primary endpoint was evaluation of the maximum tolerated dose (MTD) of quizartinib. Secondary endpoints included preliminary evidence of antitumor activity and determination of the pharmacokinetic and pharmacodynamic parameters of quizartinib. RESULTS: Thirteen patients were enrolled. Five patients received a starting dose of quizartinib 135 mg/day; dose-limiting toxicities (DLTs) of grade 3 pancytopenia, asymptomatic grade 3 QTc prolongation, and febrile neutropenia were observed in 1 patient each at this dose. A lower dose of quizartinib (90 mg/day [n = 8]) was administered without DLTs. The most common treatment-related treatment-emergent adverse events (AEs) were fatigue (n = 7, 54%), dysgeusia (n = 5, 38%), neutropenia (n = 3, 23%), and QTc prolongation (n = 3, 23%). Overall, all patients experienced at least 1 AE, and 4 experienced serious AEs (2 patients each in the 135-mg and 90-mg dose groups) including hematologic AEs, infections, and gastrointestinal disorders. Six patients (including 3 patients with gastrointestinal stromal tumors [GIST]) had a best response of stable disease. CONCLUSION: The MTD of quizartinib in patients with advanced solid tumors was 90 mg/day. Overall, the safety and tolerability of quizartinib were manageable, with no unexpected AEs. Quizartinib monotherapy had limited evidence of activity in this small group of patients with advanced solid tumors. TRIAL REGISTRATION: Clinical Trials Registration Number: NCT01049893 ; First Posted: January 15, 2010.


Assuntos
Antineoplásicos/administração & dosagem , Benzotiazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzotiazóis/efeitos adversos , Benzotiazóis/farmacocinética , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/enzimologia , Neoplasias/patologia , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Estados Unidos , Tirosina Quinase 3 Semelhante a fms/metabolismo
8.
Contact Dermatitis ; 79(4): 213-217, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29974480

RESUMO

BACKGROUND: Common pesticides used in the region by agricultural workers may cause contact allergy. METHODS: Thirty agricultural workers with a history of pesticide exposure and dermatitis involving the face, neck, trunk or extremities, and 20 controls comprising 2 groups of 10 subjects each, group 1 with dermatitis and no exposure to pesticides, and group 2 with neither exposure to pesticides nor dermatitis, were patch tested with 10 pesticides commonly used in the region by use of the Finn Chamber method. RESULTS: The 30 patients, 20 of whom were male, aged 30-77 years, had dermatitis for 1 month to 18 years, with relapses and remissions. Seasonal exacerbation was present in 18 patients. Six patients attributed aggravation of their dermatitis to pesticide exposure, and 2 of these reacted positively to propiconazole. Positive patch test reactions to pesticides occurred in 10 patients, but not in controls. Thiuram was the commonest sensitizer (4 patients). Three patients were sensitized to propiconazole, and 2 patients reacted positively to metaldehyde. Formaldehyde, mercaptobenzothiazole, cypermethrin and isoproturon gave positive reactions in 1 patient each. CONCLUSION: The sensitizing potential of pesticides remains a concern. Apparently, pesticide contact dermatitis is more common than expected, but remains under-reported, as the implicated pesticides vary across regions and according to the crop patterns.


Assuntos
Dermatite Alérgica de Contato/etiologia , Dermatite Ocupacional/etiologia , Fazendeiros , Praguicidas/efeitos adversos , Acetaldeído/efeitos adversos , Acetaldeído/análogos & derivados , Adulto , Idoso , Benzotiazóis/efeitos adversos , Estudos de Casos e Controles , Dermatite Alérgica de Contato/diagnóstico , Dermatite Ocupacional/diagnóstico , Feminino , Formaldeído/efeitos adversos , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Testes do Emplastro , Compostos de Fenilureia/efeitos adversos , Piretrinas/efeitos adversos , Compostos de Sulfidrila/efeitos adversos , Tiram/efeitos adversos , Triazóis/efeitos adversos
10.
Blood ; 132(6): 598-607, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-29875101

RESUMO

This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3-internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as FLT3-ITD-mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia's formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day.


Assuntos
Antineoplásicos/administração & dosagem , Benzotiazóis/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Terapia de Salvação , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Benzotiazóis/efeitos adversos , Benzotiazóis/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Gastroenteropatias/induzido quimicamente , Duplicação Gênica , Cardiopatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Sequências de Repetição em Tandem/genética , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética
11.
Occup Environ Med ; 75(7): 494-500, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29848553

RESUMO

BACKGROUND: Controversy exists as to the health effects of exposure to asphalt and crumb rubber modified (CRM) asphalt, which contains recycled rubber tyres. OBJECTIVE: To assess exposures and effects on airway symptoms, lung function and inflammation biomarkers in conventional and CRM asphalt road pavers. METHODS: 116 conventional asphalt workers, 51 CRM asphalt workers and 100 controls were investigated. A repeated-measures analysis included 31 workers paving with both types of asphalt. Exposure to dust, nitrosamines, benzothiazole and polycyclic aromatic hydrocarbon (PAH) was measured in worksites. Self-reported symptoms, spirometry test and blood sampling were conducted prework and postwork. Symptoms were further collected during off-season for asphalt paving. RESULTS: Dust, PAHs and nitrosamine exposure was highly varied, without difference between conventional and CRM asphalt workers. Benzothiazole was higher in CRM asphalt workers (p<0.001). Higher proportions of asphalt workers than controls reported eye symptoms with onset in the current job. Decreased lung function from preworking to postworking was found in CRM asphalt workers and controls. Preworking interleukin-8 was higher in CRM asphalt workers than in the controls, followed by a decrement after 4 days of working. No differences in any studied effects were found between conventional and CRM asphalt paving. CONCLUSION: CRM asphalt workers are exposed to higher benzothiazole. Further studies are needed to identify the source of nitrosamines in conventional asphalt. Mild decrease in lung function in CRM asphalt workers and work-related eye symptoms in both asphalt workers were observed. However, our study did not find strong evidence for severe respiratory symptoms and inflammation response among asphalt workers.


Assuntos
Hidrocarbonetos , Inflamação , Pulmão/efeitos dos fármacos , Exposição Ocupacional , Ocupações , Doenças Respiratórias , Borracha , Adulto , Poluentes Ocupacionais do Ar/efeitos adversos , Poluentes Ocupacionais do Ar/sangue , Benzotiazóis/efeitos adversos , Benzotiazóis/sangue , Biomarcadores/sangue , Poeira , Olho/efeitos dos fármacos , Humanos , Hidrocarbonetos/efeitos adversos , Inflamação/sangue , Inflamação/epidemiologia , Exposição por Inalação/efeitos adversos , Exposição por Inalação/análise , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Nitrosaminas/efeitos adversos , Nitrosaminas/sangue , Doenças Profissionais/sangue , Doenças Profissionais/epidemiologia , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/sangue , Doenças Respiratórias/sangue , Doenças Respiratórias/epidemiologia , Borracha/efeitos adversos , Local de Trabalho , Adulto Jovem
13.
Dermatitis ; 29(2): 66-76, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29494385

RESUMO

BACKGROUND: Rubber accelerators play a significant role in glove-related occupational contact dermatitis, especially among health care workers. Currently, there is limited information readily available outlining the accelerators used in specific medical examination and surgical gloves. OBJECTIVE: The aim of this study was to ascertain the accelerators used in medical examination and surgical gloves for major glove manufacturers within the United States. METHODS: An initial Internet-based search was performed to establish relevant manufacturers and product lines, with subsequent inquiry with each corresponding company regarding accelerators used in each medical and surgical glove line. RESULTS: Eleven glove manufacturers were identified and contacted. Responses were obtained from all manufacturers, but because of legal limitations, changes in product lines, or inability to supply necessary data, only 8 companies were able to be included in the final analysis, totaling data for 190 gloves. Carbamates were the most common accelerator, used in 90.5% (172/190) of gloves, whereas thiurams were used in only 11 gloves (5.8%). Eight companies surveyed are now advertising and offering touted accelerator-free gloves. CONCLUSIONS: Accelerators are used in most examination and surgical gloves; however, manufacturers are now expanding their product offerings to include accelerator-free options.


Assuntos
Benzotiazóis/efeitos adversos , Carbamatos , Luvas Cirúrgicas , Borracha/química , Tiram , Carbamatos/efeitos adversos , Dermatite Alérgica de Contato/etiologia , Dermatite Ocupacional/etiologia , Luvas Cirúrgicas/efeitos adversos , Guanidinas/efeitos adversos , Dermatoses da Mão/etiologia , Setor de Assistência à Saúde , Humanos , Tiram/efeitos adversos , Estados Unidos
15.
Contact Dermatitis ; 78(1): 12-17, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29044554

RESUMO

BACKGROUND: In 2015 and 2016, female patients in Flanders consulted a dermatologist because they developed skin lesions after wearing a specific brand of canvas shoes. OBJECTIVES: To identify the culprit allergen in the shoes. METHODS: Eighteen young females aged 14-22 years presented with itching and erythematous to purple-coloured eczematous lesions on both feet. They were patch tested by 10 dermatologists with the European baseline series. Some patients underwent testing with additional series. Pieces of the shoe fabrics were tested in 11 of 18 patients. Chemical analysis of the shoe materials was performed. Finally, patients were tested with a thin-layer chromatogram of the shoe extracts and dilutions of the suspected rubber compound. RESULTS: All 18 patients showed positive reactions to thiuram mix. Ten of 11 patients reacted to a piece of shoe fabric. Chemical analysis showed the presence of dimethylthiocarbamylbenzothiazole sulfide (DMTBS). No thiurams were detected. Four patients tested with the chromatogram developed positive reactions to DMTBS. Positive reactions to low concentrations were observed in the 4 patients tested with a DMTBS dilution series; one patient reacted to 0.00001% in acetone. CONCLUSIONS: DMTBS, the culprit allergen, is a component formed during rubber vulcanization that probably cross-reacts with the thiuram mix.


Assuntos
Benzotiazóis/efeitos adversos , Dermatite Alérgica de Contato/etiologia , Sapatos/efeitos adversos , Têxteis/efeitos adversos , Tiocarbamatos/efeitos adversos , Adolescente , Cromatografia em Camada Delgada , Feminino , Humanos , Testes do Emplastro , Tiram/efeitos adversos , Adulto Jovem
16.
Am J Hematol ; 93(2): 222-231, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29090473

RESUMO

FLT3-ITD-mutated acute myeloid leukemia (AML) has very high risk of relapse and is associated with poor outcome following allogeneic hematopoietic-cell transplant (allo-HCT). This two-part, phase 1, multicenter, open-label, sequential-group, dose-escalation study aimed to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and safety/tolerability of quizartinib, a selective and highly potent FLT3 inhibitor, when administered as maintenance therapy after allo-HCT. Thirteen subjects with documented FLT3-ITD-mutated AML in morphological remission following allo-HCT received one of two quizartinib dihydrochloride dose levels (DL): 40 mg/d (DL1; n = 7) and 60 mg/d (DL2; n = 6), administered orally in 28-day cycles for up to 24 cycles. Median age of participants was 43 years. All subjects received human leukocyte antigen (HLA)-matched allo-HCT. One subject treated at DL1 and 1 treated at DL2 had DLTs that required drug interruption (grade 3 gastric hemorrhage and grade 3 anemia, respectively). Ten subjects (77%) received quizartinib for >1 year; 5 (38%) completed 24 cycles. Four subjects (31%) discontinued quizartinib due to adverse events. One subject (8%) experienced relapse during cycle 1 and discontinued treatment. Most common grade 3/4 adverse events were neutropenia (23%), anemia (15%), leukopenia (15%), lymphopenia (15%), and thrombocytopenia (15%). This study demonstrated acceptable tolerability and early evidence of reduced relapse rate following allo-HCT with quizartinib maintenance compared to historical cohorts. No MTD was identified, but 60 mg daily was selected as highest dose for continuous daily administration based on randomized comparison of daily 30 and 60 mg doses in relapsed/refractory AML.


Assuntos
Benzotiazóis/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Adulto , Benzotiazóis/efeitos adversos , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/terapia , Quimioterapia de Manutenção/efeitos adversos , Quimioterapia de Manutenção/métodos , Dose Máxima Tolerável , Compostos de Fenilureia/efeitos adversos , Recidiva , Indução de Remissão , Transplante Homólogo , Tirosina Quinase 3 Semelhante a fms/genética
17.
Contact Dermatitis ; 78(1): 7-11, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28776709

RESUMO

BACKGROUND: During rubber vulcanization, new compounds can be formed. OBJECTIVES: To report a case of allergic shoe dermatitis in which the search for the allergen ultimately led to the identification of dimethylthiocarbamylbenzothiazole sulfide (DMTBS). METHODS: A female presented with eczema on her feet after wearing Sperry Top Sider® canvas sneakers. Patch testing was performed with the European baseline series, additional series, shoe materials, and extracts of shoe materials. Thin-layer chromatography (TLC) was performed for additional patch testing, and high-performance liquid chromatography and gas chromatography-mass spectometry were used for chemical analysis. RESULTS: Positive reactions were found to thiuram mix (+), tetramethylthiuram monosulfide (TMTM) (+), shoe material (+), and shoe extracts in eth. (++) and acetone (+). The extracts did not contain TMTM or other components of thiuram mix. TLC strips yielded a positive reaction (+) to one spot, whereas chemical analysis gave a negative result. Thereafter, a similar sneaker from another patient with shoe dermatitis was analysed, and DMBTS was identified. New extracts of the shoe of our first patient were then also shown to contain DMTBS. DMTBS as culprit allergen was confirmed by positive patch testing with a dilution series with DMTBS. CONCLUSION: DMBTS was identified as the culprit allergen in shoe dermatitis, giving rise to compound allergy. The positive reaction to TMTM was considered to represent cross-reactivity.


Assuntos
Benzotiazóis/efeitos adversos , Dermatite Alérgica de Contato/etiologia , Dermatoses do Pé/induzido quimicamente , Sapatos/efeitos adversos , Têxteis/efeitos adversos , Tiocarbamatos/efeitos adversos , Adolescente , Benzotiazóis/análise , Cromatografia em Camada Delgada , Eczema/induzido quimicamente , Feminino , Humanos , Testes do Emplastro , Tiocarbamatos/análise
18.
Am J Hematol ; 93(2): 213-221, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29139135

RESUMO

Novel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline-based induction/consolidation chemotherapy. Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single-agent activity in relapsed or refractory (R/R) AML. This phase 1, open-label, sequential group dose-escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML). Nineteen patients unselected for FLT3 mutational status received one of three quizartinib dihydrochloride dose levels (DL): 60 mg/d for 7 days (DL1; n = 6), 60 mg/d for 14 days (DL2; n = 7), and 40 mg/d for 14 days (DL-1; n = 6); administered orally starting on day 4 of chemotherapy. Median age was 43.8 years. Ten patients completed induction and consolidation. Three patients experienced dose-limiting toxicities (DLTs): 2 at DL2 (1 pericardial effusion; 1 febrile neutropenia, decreased platelet count, and QT prolongation); 1 at DL-1 (pericarditis). Maximum tolerated dose (MTD) was identified as DL-1. Most common grade 3/4 adverse events were febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), and anemia (26%). There were no apparent additional toxicities with addition of quizartinib to chemotherapy although grade ≤1 QT prolongation was observed at MTD. Sixteen patients (84%) achieved a response; 14 (74%) composite complete response; 2 (11%) morphologic leukemia-free state. The phase 3 QuANTUM-First trial (NCT02668653) is further evaluating the effect of quizartinib plus SOC chemotherapy in ndAML FLT3-ITD mutated patients.


Assuntos
Benzotiazóis/administração & dosagem , Quimioterapia Combinada/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Adulto , Anemia/induzido quimicamente , Benzotiazóis/efeitos adversos , Quimioterapia de Consolidação/métodos , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Compostos de Fenilureia/efeitos adversos , Indução de Remissão/métodos , Trombocitopenia/induzido quimicamente
19.
Eur J Cancer ; 87: 131-139, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29145039

RESUMO

PURPOSE: Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. METHODS: This was a phase I dose-escalation (3 + 3 design [50-740 mg/m2]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort. RESULTS: In total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m2, five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number. CONCLUSION: The MTD of once-weekly SAR125844 was 570 mg/m2; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. CLINICAL TRIAL REGISTRATION NUMBER: NCT01391533.


Assuntos
Antineoplásicos/administração & dosagem , Benzotiazóis/administração & dosagem , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Amplificação de Genes , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Ureia/análogos & derivados , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzotiazóis/efeitos adversos , Benzotiazóis/farmacocinética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Europa (Continente) , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Ureia/administração & dosagem , Ureia/efeitos adversos , Ureia/farmacocinética
20.
Postgrad Med ; 129(7): 667-675, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28818004

RESUMO

Restless legs syndrome (RLS) is a chronic disorder causing clinically significant discomfort to approximately 3% of adults. Although RLS was first identified centuries ago, our understanding of this disorder, its causes, and its treatments is still evolving. In particular, our knowledge of the potential negative effects of RLS treatments, including dopaminergic augmentation, continues to expand. Augmentation, which refers to a paradoxical treatment-related increase in RLS symptoms, has been associated with all three dopamine agonists approved for the treatment of RLS - rotigotine, pramipexole, and ropinirole. This review presents key information on prevention and treatment of dopaminergic augmentation from the recently published consensus-based guidelines issued by the International RLS Study Group task force in conjunction with the European RLS Study Group and the RLS Foundation for first-line treatment of RLS/Willis-Ekbom disease. If dopamine agonists are used to treat RLS, it is recommended that the dosage should be kept as low as possible without exceeding the maximum dose recommended for RLS treatment. As the frequency of augmentation with the rotigotine patch may only be slightly lower than that associated with pramipexole or ropinirole, medications that are effective and have little risk of augmentation, such as alpha-2-delta ligands, may be considered for initial RLS treatment. In addition, we present our clinical experience with treating patients with dopaminergic augmentation by highlighting 2 case studies and practical considerations when treating different patient populations. Applying current RLS augmentation diagnosis and treatment guidelines, as well as collecting detailed histories of worsening RLS symptoms, is critical for patient safety and effective management of RLS augmentation.


Assuntos
Benzotiazóis/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Indóis/uso terapêutico , Ligantes , Síndrome das Pernas Inquietas/diagnóstico , Síndrome das Pernas Inquietas/tratamento farmacológico , Tetra-Hidronaftalenos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzotiazóis/efeitos adversos , Agonistas de Dopamina/efeitos adversos , Feminino , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Tetra-Hidronaftalenos/efeitos adversos , Resultado do Tratamento
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