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1.
Molecules ; 26(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299453

RESUMO

Bisphenol Z (BPZ), bisphenol S (BPS), bisphenol C (BPC), and bisphenol F (BPF) had been widely used as alternatives to bisphenol A (BPA), but the toxicity data of these bisphenol analogues were very limited. In this study, the joint toxicity of BPZ, BPS, BPC, and BPF to zebrafish (Danio rerio) was investigated. The median half lethal concentrations (LC50) of BPZ, BPS, BPC, and BPF to zebrafish for 96 h were 6.9 × 105 µM, 3.9 × 107 µM, 7.1 × 105 µM, and1.6 × 106 µM, respectively. The joint toxicity effect of BPF-BPC (7.7 × 105-3.4 × 105µM) and BPZ-BPC (3.4 × 105-3.5 × 105µM) with the same toxic ratio showed a synergistic effect, which may be attributed to enzyme inhibition or induction theory. While the toxicity effect of the other two bisphenol analogue combined groups and multi-joint pairs showed an antagonistic effect due to the competition site, other causes need to be further explored. Meanwhile, the expression levels of the estrogen receptor genes (ERα, ERß1) and antioxidant enzyme genes (SOD, CAT, GPX) were analyzed using a quantitative real-time polymerase chain reaction in zebrafish exposure to LC50 of BPZ, BPS, BPC, and BPF collected at 24, 48, 72, and 96 h. Relative expression of CAT, GPX, and ERß1 mRNA declined significantly compared to the blank control, which might be a major cause of oxidant injury of antioxidant systems and the disruption of the endocrine systems in zebrafish.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/toxicidade , Animais , Cicloexanos/efeitos adversos , Fenóis/efeitos adversos , Sulfonas/efeitos adversos , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/efeitos dos fármacos , Proteínas de Peixe-Zebra/metabolismo
2.
Fertil Steril ; 116(3): 820-832, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34238571

RESUMO

OBJECTIVE: To explore windows of vulnerability to prenatal urinary phenol concentrations and preterm birth. DESIGN: Prospective cohort. SETTING: A large fertility center in Boston, Massachusetts. PATIENT(S): A total of 386 mothers who sought fertility treatment and gave birth to a singleton between 2005 and 2018. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Singleton live birth with gestational age <37 completed weeks. RESULT(S): Compared with women with non-preterm births, urinary bisphenol A (BPA) concentrations were higher across gestation among women with preterm births, particularly during mid-to-late pregnancy and among those with female infants. Second trimester BPA concentrations were associated with preterm birth (Risk Ratio [RR] 1.24; 95%CI: 0.92, 1.69), which was primarily driven by female (RR 1.40; 95%CI: 1.04, 1.89) and not male (RR 0.85; 95%CI 0.50, 1.46) infants. First trimester paraben concentrations were also associated with preterm birth (RR 1.17; 95%CI: 0.94, 1.46) and similarly the association was only observed for female (RR 1.46; 95% CI: 1.10, 1.94) and not male infants (RR 0.94; 95%CIC: 0.72, 1.23). First trimester urinary bisphenol S concentrations showed a suggested risk of preterm birth (RR 1.25; 95%CI: 0.82, 1.89), although the small case numbers precluded sex-specific examination. CONCLUSION(S): We found preliminary evidence of associations between mid-to-late pregnancy BPA and early pregnancy paraben concentrations with preterm birth among those with female infants only. Preterm birth risk may be compound, sex, and window specific. Given the limited sample size of this cohort, results should be confirmed in larger studies, including fertile populations.


Assuntos
Infertilidade/urina , Fenóis/efeitos adversos , Fenóis/urina , Nascimento Prematuro/induzido quimicamente , Adulto , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/urina , Biomarcadores/urina , Feminino , Fertilidade , Idade Gestacional , Humanos , Infertilidade/diagnóstico , Infertilidade/fisiopatologia , Infertilidade/terapia , Nascido Vivo , Masculino , Parabenos/efeitos adversos , Parabenos/metabolismo , Gravidez , Estudos Prospectivos , Técnicas de Reprodução Assistida , Medição de Risco , Fatores de Risco , Fatores Sexuais , Sulfonas/efeitos adversos , Sulfonas/urina , Resultado do Tratamento
3.
Medicine (Baltimore) ; 100(26): e26449, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34190169

RESUMO

RATIONALE: Anaplastic lymphoma kinase (ALK) inhibitors have been approved for patients with ALK-rearrangement lung cancer. The effect is superior to the standard first-line therapy of pemetrexed plus platinum-based chemotherapy. However, ALK inhibitors are associated with rare and sometimes fatal adverse events. Organizing pneumonitis (OP) is a rare and serious adverse event usually caused by ceritinib, and it is easily misdiagnosed as infectious pneumonia, metastasis, or cancer progression. PATIENT CONCERNS: A 56-year-old female presented with chest tightness and dyspnea for more than 10 days. She was previously healthy with no significant medical history. Workup including chest computed tomography (CT), pathological examination of a biopsy specimen, and next-generation sequencing was consistent with a diagnosis of IVA ALK-rearrangement lung adenocarcinoma. She was treated with pemetrexed plus platinum-based chemotherapy and crizotinib concurrently, followed by maintenance therapy with crizotinib alone and she had an almost complete response. However, about 26 months after beginning treatment she developed multiple brain metastases. Crizotinib was discontinued and she was begun on ceritinib. After about 3 months the brain metastases had almost complete response. After 5 months of ceritinib, however, multiple patchy lesions appeared in the bilateral upper lungs. DIAGNOSES: Treatment with antibiotics had no effect and blood and sputum cultures are negative. A CT-guided biopsy of the upper lung was performed, and pathological hematoxylin-eosin staining and immunohistochemical studies were consistent with OP. INTERVENTIONS: Ceritinib was discontinued, she was begun on prednisone 0.5 mg/kg orally every day, and regular follow-up is necessary. OUTCOMES: CT of the chest 2 and 4 weeks after beginning prednisone showed the lung lesions to be gradually resolving, and she was continued on prednisone for 2 months and gradually reduced the dose of prednisone every 2 weeks. No related adverse events were occurred in patient. LESSONS: OP must be differentiated from infectious pneumonia, metastasis, or cancer progression. The mechanism of OP is still unknown and needs further research. Biopsy plays a role in making a diagnosis of OP. In our patient, discontinuing ceritinib and treating her with prednisone resulted in a good outcome.


Assuntos
Adenocarcinoma de Pulmão , Quinase do Linfoma Anaplásico , Pneumonia em Organização Criptogênica , Neoplasias Pulmonares , Prednisona/administração & dosagem , Pirimidinas , Sulfonas , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/fisiopatologia , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/uso terapêutico , Biópsia/métodos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Crizotinibe/uso terapêutico , Pneumonia em Organização Criptogênica/induzido quimicamente , Pneumonia em Organização Criptogênica/patologia , Pneumonia em Organização Criptogênica/terapia , Substituição de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Pessoa de Meia-Idade , Pemetrexede/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sulfonas/administração & dosagem , Sulfonas/efeitos adversos , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
4.
Nutrients ; 13(5)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34062990

RESUMO

Obesogenic endocrine-disrupting chemicals, such as bisphenol A (BPA) and its analogue bisphenol S (BPS), seem to play an important role in the development of obesity, although contradictory results have been reported. The aim of the present study was to conduct a gender analysis of the factors associated with exposure to dietary bisphenols in 585 Spanish adolescents. Dietary BPA and BPS exposure was assessed using a food frequency questionnaire. Foods and macronutrients accounting for more than 95% of energy intake were selected for analysis. Stepwise regression was used to estimate the foods that most contributed to dietary bisphenol exposure in the sample. Gender-related factors associated with greater dietary bisphenol exposure were evaluated using multivariate logistic regression models. Canned tuna was the main dietary source of BPA and BPS in both adolescent boys and girls. Overweight/obese girls showed a higher risk of high dietary exposure to BPA (odds ratio (OR): 3.38, 95% confidence interval (CI): 1.25-9.07) and total bisphenols (OR: 2.81, 95% CI: 1.03-7.67) in comparison with girls with a BMI lower than 25 kg/m2. Present results indicate a positive association of dietary exposure to both total bisphenols and BPA with being overweight/obese in adolescent girls.


Assuntos
Compostos Benzidrílicos/análise , Exposição Dietética/análise , Obesidade Pediátrica/etiologia , Fenóis/análise , Fatores Sexuais , Sulfonas/análise , Adolescente , Compostos Benzidrílicos/efeitos adversos , Índice de Massa Corporal , Inquéritos sobre Dietas , Exposição Dietética/efeitos adversos , Ingestão de Alimentos , Feminino , Humanos , Masculino , Razão de Chances , Obesidade Pediátrica/epidemiologia , Fenóis/efeitos adversos , Análise de Regressão , Fatores de Risco , Espanha/epidemiologia , Sulfonas/efeitos adversos
5.
Genes (Basel) ; 12(2)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33672423

RESUMO

Bisphenol S (BPS) is used as an alternative plasticizer to Bisphenol A (BPA), despite limited knowledge of potential adverse effects. BPA exhibits endocrine disrupting effects during development. This article focuses on the impact of bisphenols during oocyte maturation. Connexins (Cx) are gap junctional proteins that may be affected by bisphenols, providing insight into their mechanism during development. Cxs 37 and 43 are crucial in facilitating cell communication between cumulus cells and oocytes. Cumulus-oocyte complexes (COCs), denuded oocytes, and cumulus cells were exposed to 0.05 mg/mL BPA or BPS for 24 h. Both compounds had no effect on Cx43. Cumulus cells exhibited a significant increase in Cx37 expression following BPA (p = 0.001) and BPS (p = 0.017) exposure. COCs treated with BPA had increased Cx37 protein expression, whilst BPS showed no effects, suggesting BPA and BPS act through different mechanisms. Experiments conducted in in vitro cultured cumulus cells, obtained by stripping germinal vesicle oocytes, showed significantly increased expression of Cx37 in BPA, but not the BPS, treated group. BPA significantly increased Cx37 protein expression, while BPS did not. Disrupted Cx37 following BPA exposure provides an indication of possible effects of bisphenols on connexins during the early stages of development.


Assuntos
Compostos Benzidrílicos/farmacologia , Conexina 43/genética , Conexinas/genética , Fenóis/farmacologia , Sulfonas/farmacologia , Animais , Compostos Benzidrílicos/efeitos adversos , Bovinos , Células do Cúmulo/efeitos dos fármacos , Disruptores Endócrinos/efeitos adversos , Disruptores Endócrinos/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Técnicas de Maturação in Vitro de Oócitos , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Fenóis/efeitos adversos , Plastificantes/efeitos adversos , Plastificantes/farmacologia , Sulfonas/efeitos adversos
6.
Cancer Chemother Pharmacol ; 87(4): 475-486, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33394101

RESUMO

PURPOSE: Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug-drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively. METHODS: This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily. RESULTS: Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC. CONCLUSION: Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Citocromo P-450 CYP2C9/fisiologia , Citocromo P-450 CYP3A/fisiologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Adulto , Idoso , Quinase do Linfoma Anaplásico/análise , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos Cross-Over , Interações Medicamentosas , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Midazolam/farmacocinética , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Sulfonas/efeitos adversos , Sulfonas/farmacocinética , Varfarina/farmacocinética , Adulto Jovem
7.
Mod Rheumatol ; 31(1): 53-60, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32075475

RESUMO

OBJECTIVES: Many patients with rheumatoid arthritis (RA) are not able to achieve long-term disease remission. This phase 2a study (NCT02884635) evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of the novel, oral, gonadotropin-releasing hormone antagonist, ASP1707, in combination with methotrexate (MTX) for treatment of RA. METHODS: Postmenopausal women with RA who had been receiving MTX for ≥90 days were randomized to ASP1707 30 mg twice daily or placebo for 12 weeks. The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Secondary endpoints included: ACR20, ACR50, and ACR70 response rates; disease activity score (DAS)28-CRP; DAS28-ESR; Tender or Swollen Joint Counts; and remission rates. RESULTS: Of 105 patients screened, 72 were randomized to ASP1707 30 mg twice daily (n = 37) or placebo (n = 35). ASP1707 did not improve ACR20, ACR50, or ACR70 response rates at any time point and did not improve any secondary efficacy endpoint. Plasma luteinizing hormone (LH) concentration decreased >90% in >90% of patients receiving ASP1707, with a rapid decrease to <1 IU/L at week 1 that remained stable throughout the treatment. CONCLUSION: In the current study, ASP1707 did not demonstrate a clinical benefit.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Imidazóis/uso terapêutico , Metotrexato/uso terapêutico , Pós-Menopausa , Sulfonas/uso terapêutico , Idoso , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Imidazóis/efeitos adversos , Pessoa de Meia-Idade , Sulfonas/efeitos adversos , Resultado do Tratamento
8.
Drugs R D ; 21(1): 65-78, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33331996

RESUMO

BACKGROUND AND OBJECTIVE: Anaplastic lymphoma kinase gene rearrangements (ALKr) resulting in EML4-ALK proteins occur in a subset of solid tumors and are targeted by ALK inhibitors. Given the development of drug resistance to ALK inhibitors, ALK inhibitors with different kinase selectivity are required. METHODS: This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. Between 1 June 2011 and 20 January 2014, 29 patients received different daily doses of ASP3026 in the escalation (25 mg, n = 3; 50 mg, n = 3; 75 mg, n = 3; 125 mg, n = 4; 200 mg, n = 3; or 325 mg, n = 7) and expansion (200 mg, n = 6) cohorts. RESULTS: Three patients had DLTs at the 325-mg dose: cataract exacerbation, increased aspartate transaminase and alanine transaminase, and impaired hepatic function (all Grade 3 severity). Thus, the maximum tolerated dose was 200 mg. The treatment-emergent adverse event incidence was 100%; the most common events were nausea (n = 8, 27.6%), decreased appetite (n = 10, 34.5%), and fatigue (n = 9, 31.0%) of mild or moderate severity. Six patients were positive for ALK protein and three had ALKr. Two patients achieved partial responses: one with Ewing sarcoma (75-mg dose group) and one with an ALKr-positive inflammatory myofibroblastic tumor (125-mg dose group). CONCLUSION: ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile. CLINICAL TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Sulfonas/administração & dosagem , Triazinas/administração & dosagem , Administração Oral , Adulto , Idoso , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Apetite/efeitos dos fármacos , Grupo com Ancestrais do Continente Asiático , Relação Dose-Resposta a Droga , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Miosite/tratamento farmacológico , Miosite/enzimologia , Miosite/genética , Náusea/induzido quimicamente , Neoplasias/enzimologia , Neoplasias/genética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/enzimologia , Sarcoma de Ewing/genética , Sulfonas/efeitos adversos , Sulfonas/sangue , Sulfonas/farmacocinética , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/sangue , Triazinas/farmacocinética
9.
Dermatol Online J ; 26(11)2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33342182

RESUMO

Aquagenic wrinkling of the palms (AWP) is a rare, acquired condition of the skin, defined by transient rapidly developing white to translucent papules on palms and/or soles after brief exposure to water. Aquagenic wrinkling of the palms is associated with cystic fibrosis (CF). Therefore, the diagnosis of AWP can be important. Etiopathogenesis of AWP is still unclear. Treatment is often unsatisfactory and can be very challenging. This article contributes to the knowledge of AWP as we describe two new cases of aquagenic wrinkling of the palms: one patient with familial history of CF and one patient with AWP that was presumed to be induced by use of non-steroidal anti-inflammatory drugs. In addition, we present a review of the literature on drug-induced AWP.


Assuntos
Mãos/patologia , Pele/patologia , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Feminino , Humanos , Ibuprofeno/efeitos adversos , Imersão , Lactonas/efeitos adversos , Masculino , Sulfonas/efeitos adversos , Água
10.
Sci Rep ; 10(1): 16773, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033286

RESUMO

Ceritinib is a selective anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with unresectable advanced and/or recurrent ALK fusion gene-positive non-small cell lung cancer (NSCLC). As per the approval condition in Japan, this post-marketing surveillance (PMS) study evaluated the clinical safety (including adverse events [AEs], adverse drug reactions [ADRs] and priority investigation items) and efficacy (including ORR and PFS) of ceritinib in Japanese patients. Interim analysis was conducted ~ 2 years after the start of this non-interventional, multicentre, uncontrolled, open-label, special drug-use investigation and results are reported from March 28, 2016 to April 28, 2018. Each patient was followed up for 1 year. Most patients started treatment with 750 mg ceritinib. Safety profile was similar to that observed at the time of approval. No new AEs or ADRs with incidences higher than that at approval were identified. The rate of gastrointestinal ADRs (nausea, vomiting and diarrhoea) was 73.64%. Meaningful efficacy was observed in both post-crizotinib and post-alectinib settings, with ORR of 29.55% (95% CI 20.29-40.22) and disease control rate of 53.41% (95% CI 42.46-64.12). No concerns regarding the safety and efficacy of ceritinib were identified. No new measures, including modification of the PMS study protocol, are considered necessary.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Japão , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , Intervalo Livre de Progressão , Pirimidinas/efeitos adversos , Sulfonas/efeitos adversos
11.
Environ Health ; 19(1): 93, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32867778

RESUMO

BACKGROUND: Bisphenol A (BPA), one of the highest-volume chemicals produced worldwide, has been identified as an endocrine disruptor. Many peer-reviewing studies have reported adverse effects of low dose BPA exposure, particularly during perinatal period (gestation and/or lactation). We previously demonstrated that perinatal oral exposure to BPA (via gavage of mothers during gestation and lactation) has long-term consequences on immune response and intestinal barrier functions. Due to its adverse effects on several developmental and physiological processes, BPA was removed from consumer products and replaced by chemical substitutes such as BPS or BPF, that are structurally similar and not well studied compare to BPA. Here, we aimed to compare perinatal oral exposure to these bisphenols (BPs) at two doses (5 and 50 µg/kg of body weight (BW)/day (d)) on immune response at intestinal and systemic levels in female offspring mice at adulthood (Post Natal Day PND70). METHODS: Pregnant female mice were orally exposed to BPA, BPS or BPF at 5 or 50 µg/kg BW/d from 15th day of gravidity to weaning of pups at Post-Natal Day (PND) 21. Humoral and cellular immune responses of adult offspring (PND70) were analysed at intestinal and systemic levels. RESULTS: In female offspring, perinatal oral BP exposure led to adverse effects on intestinal and systemic immune response that were dependant of the BP nature (A, S or F) and dose of exposure. Stronger impacts were observed with BPS at the dose of 5 µg/kg BW/d on inflammatory markers in feces associated with an increase of anti-E. coli IgG in plasma. BPA and BPF exposure induced prominent changes at low dose in offspring mice, in term of intestinal and systemic immune responses, provoking an intestinal and systemic Th1/Th17 inflammation. CONCLUSION: These findings provide, for the first time, results of long-time consequences of BPA, S and F perinatal exposure by oral route on immune response in offspring mice. This work warns that it is mandatory to consider immune markers and dose exposure in risk assessment associated to new BPA's alternatives.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Fenóis/efeitos adversos , Sulfonas/efeitos adversos , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Lactação/efeitos dos fármacos , Exposição Materna , Camundongos , Camundongos Endogâmicos C3H , Gravidez/efeitos dos fármacos
12.
J Insect Physiol ; 125: 104086, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628959

RESUMO

Calcium is an important intracellular second messenger involved in several processes such as the transduction of odour signals and neuronal excitability. Despite this critical role, relatively little information is available with respect to the impact of insecticides on the dynamics of intracellular calcium homeostasis in olfactory neurons. For the first time here, physiological stimuli (depolarizing current or pheromone) were shown to elicit calcium transients in peripheral neurons from the honey bee antenna. In addition, neurotoxic xenobiotics (the first synthetic phthalic diamide insecticide flubendiamide or botanical alkaloids ryanodine and caffeine) do interfere with normal calcium homeostasis. Our in vitro experiments show that these three xenobiotics can induce sustained abnormal calcium transients in antennal neurons. The present results provide a new insight into the toxicity of diamides, showing that flubendiamide drastically impairs calcium homeostasis in antennal neurons. We propose that a calcium imaging assay should provide an efficient tool dedicated to the modern assessment strategies of insecticides toxicity.


Assuntos
Antenas de Artrópodes/efeitos dos fármacos , Benzamidas/efeitos adversos , Cálcio/metabolismo , Inseticidas/efeitos adversos , Neurônios/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sulfonas/efeitos adversos , Animais , Antenas de Artrópodes/fisiologia , Neurônios/fisiologia
13.
Leuk Res ; 94: 106369, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32442785

RESUMO

Phase 1 results from a Phase 1/2 study comprise 18 patients with myelodysplastic syndromes (MDS; n = 9), acute myeloid leukemia (AML; n = 8), and chronic myelomonocytic leukemia (CMML; n = 1) who were either hypomethylating agent naïve (n = 10) or relapsed/refractory following prior hypomethylating agent therapy (n = 8) (NCT01926587). Patients received oral rigosertib, an inhibitor of Ras-effector pathways, in 3 successive cohorts (140 mg twice daily, 280 mg twice daily, or 840 mg/day [560 mg morning/280 mg evening]) for 3 weeks of a 4-week cycle. Patients received parenteral azacitidine (75 mg/m2/day × 7 days) during the second week; the cycle repeated every 4 weeks. The combination was well tolerated for a median of 4 (range 1-41) cycles, with 72% of patients experiencing ≥1 serious adverse events. No dose-limiting toxicities were observed. Thus, no maximum tolerated dose was reached. The most frequently reported adverse events were diarrhea (50%), constipation, fatigue, and nausea (each 44%), and pneumonia and back pain (each 33%). Sequential administration demonstrated an overall response rate of 56% in evaluable patients, with responses observed in 7/9 MDS/CMML patients (78%) and 2/7 AML patients (29%). Further clinical studies are warranted to investigate this doublet therapy in patients with myeloid malignancies.


Assuntos
Azacitidina/administração & dosagem , Glicina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Sulfonas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Azacitidina/efeitos adversos , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/patologia , Sulfonas/efeitos adversos
14.
J Clin Pharm Ther ; 45(4): 743-754, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32369239

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Ceritinib is a new, oral, potent and selective second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the Food and Drug Administration of the United States in April 2014. It is active in crizotinib-resistant patients, especially in patients with non-small cell lung cancer (NSCLC) and brain metastasis. The aim of this study was to analyse the effects and side effects of ceritinib in ALK-rearranged NSCLC. METHODS: We searched articles published from January 1980 to March 2019 in PubMed, EMBASE, Cochrane Library and Web of Science. The pooled estimate and 95% CI were calculated with DerSimonian-Laird method and the random effect model. RESULTS AND DISCUSSION: From 15 articles, 2,598 patients were included in the meta-analysis. Eleven studies reported the ORR, and the DCR was presented in 10 studies. The ORR and DCR of ceritinib were 0.48 (95% CI, 0.39-0.57) and 0.76 (95% CI, 0.69-0.82), respectively. The PFS and OS were presented in nine and three eligible studies, respectively. The PFS and OS of ceritinib were 7.26 months (95% CI, 5.10-9.43) and 18.73 months (95% CI; 14.59-22.87). These results suggested that ceritinib can effectively treat patients with ALK-rearranged NSCLC. Diarrhoea, nausea and vomiting were the three most common AEs and occurred in 69% (95% CI 51.7-87.1%), 66% (95% CI 47.0-85.8%) and 51% (95% CI 35.9-66.8%) of patients, respectively. Considering serious gastrointestinal AEs, antiemetic and antidiarrhoeal drugs should be considered to improve a patient's tolerance to ceritinib. WHAT IS NEW AND CONCLUSION: Ceritinib is effective in the treatment of patients with ALK-rearranged NSCLC with crizotinib resistance. The DCR was up to 76%, and PFS was extended to 7.6 months. The AEs were acceptable.


Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Sulfonas/efeitos adversos , Sulfonas/uso terapêutico , Neoplasias Encefálicas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo
15.
Am J Trop Med Hyg ; 103(1): 378-393, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32314694

RESUMO

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


Assuntos
Alanina Transaminase/metabolismo , Antimaláricos/efeitos adversos , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Voluntários Saudáveis , Malária Falciparum/tratamento farmacológico , Parasitemia/tratamento farmacológico , Acrilamidas/efeitos adversos , Adamantano/efeitos adversos , Adamantano/análogos & derivados , Adulto , Aminopiridinas/efeitos adversos , Aminoquinolinas/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Transfusão de Eritrócitos , Eritrócitos/parasitologia , Feminino , Compostos Ferrosos/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Indóis/efeitos adversos , Isoquinolinas/efeitos adversos , Masculino , Metalocenos/efeitos adversos , Peróxidos/efeitos adversos , Piperazinas/efeitos adversos , Plasmodium falciparum , Primaquina/efeitos adversos , Pirimidinas/efeitos adversos , Quinolinas/efeitos adversos , Compostos de Espiro/efeitos adversos , Sulfonas/efeitos adversos , Triazóis/efeitos adversos , Adulto Jovem
16.
Cells ; 9(3)2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32111102

RESUMO

Cardiac adverse effects are among the leading causes of the discontinuation of clinical trials and the withdrawal of drugs from the market. The novel concept of 'hidden cardiotoxicity' is defined as cardiotoxicity of a drug that manifests in the diseased (e.g. ischemic/reperfused), but not in the healthy heart or as a drug-induced deterioration of cardiac stress adaptation (e.g. ischemic conditioning). Here, we aimed to test if the cardiotoxicity of a selective COX-2 inhibitor rofecoxib that was revealed during its clinical use, i.e., increased occurrence of proarrhythmic and thrombotic events, could have been revealed in early phases of drug development by using preclinical models of ischemia/reperfusion (I/R) injury. Rats that were treated with rofecoxib or vehicle for four weeks were subjected to 30 min. coronary artery occlusion and 120 min. reperfusion with or without cardioprotection that is induced by ischemic preconditioning (IPC). Rofecoxib increased overall the arrhythmias including ventricular fibrillation (VF) during I/R. The proarrhythmic effect of rofecoxib during I/R was not observed in the IPC group. Rofecoxib prolonged the action potential duration (APD) in isolated papillary muscles, which was not seen in the simulated IPC group. Interestingly, while showing hidden cardiotoxicity manifested as a proarrhythmic effect during I/R, rofecoxib decreased the infarct size and increased the survival of adult rat cardiac myocytes that were subjected to simulated I/R injury. This is the first demonstration that rofecoxib increased acute mortality due to its proarrhythmic effect via increased APD during I/R. Rofecoxib did not interfere with the cardiprotective effect of IPC; moreover, IPC was able to protect against rofecoxib-induced hidden cardiotoxicity. These results show that cardiac safety testing with simple preclinical models of I/R injury uncovers hidden cardiotoxicity of rofecoxib and might reveal the hidden cardiotoxicity of other drugs.


Assuntos
Cardiotoxicidade/complicações , Lactonas/efeitos adversos , Traumatismo por Reperfusão/complicações , Sulfonas/efeitos adversos , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/complicações , Cardiotônicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Precondicionamento Isquêmico , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Ratos Wistar
18.
Artigo em Inglês | MEDLINE | ID: mdl-31932368

RESUMO

MMV390048 is a novel antimalarial compound that inhibits Plasmodium phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and antimalarial activity of MMV390048 were determined in healthy volunteers in three separate studies. A first-in-human, double-blind, randomized, placebo-controlled, single-ascending-dose study was performed. Additionally, a volunteer infection study investigated the antimalarial activity of MMV390048 using the Plasmodium falciparum induced blood-stage malaria (IBSM) model. Due to the high pharmacokinetic variability with the powder-in-bottle formulation used in both of these studies, a third study was undertaken to select a tablet formulation of MMV390048 to take forward into future studies. MMV390048 was generally well tolerated when administered as a single oral dose up to 120 mg, with rapid absorption and a long elimination half-life. Twelve adverse events were considered to be potentially related to MMV390048 in the first-in-human study but with no obvious correlation between these and MMV390048 dose or exposure. Although antimalarial activity was evident in the IBSM study, rapid recrudescence occurred in most subjects after treatment with 20 mg MMV390048, a dose expected to be subtherapeutic. Reformulation of MMV390048 into two tablet formulations (tartaric acid and Syloid) resulted in significantly reduced intersubject pharmacokinetic variability. Overall, the results of this study suggest that MMV390048 is well tolerated in humans, and the pharmacokinetic properties of the compound indicate that it has the potential to be used for antimalarial prophylaxis or inclusion in a single-dose cure. MMV390048 is currently being tested in a phase 2a study in Ethiopian adults with acute, uncomplicated falciparum or vivax malaria monoinfection. (The three clinical trials described here were each registered with ClinicalTrials.gov as follows: first-in-human study, registration no. NCT02230579; IBSM study, registration no. NCT02281344; and formulation optimization study, registration no. NCT02554799.).


Assuntos
Aminopiridinas/farmacologia , Antimaláricos/farmacologia , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Sulfonas/farmacologia , 1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Adulto , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Ensaios Clínicos Fase I como Assunto , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Sulfonas/efeitos adversos , Sulfonas/farmacocinética
19.
Drug Saf ; 43(4): 301-318, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31916080

RESUMO

The risk of coronary events with non-steroidal anti-inflammatory drugs has been the subject of much debate since the original trial of rofecoxib raised the issue. Since then, over almost 20 years, such risks have been shown in clinical trials of long-term high-dose users, and in observational studies comparing users with non-users. The roles of cyclooxygenase (COX)-2/COX-1 selectivity and COX-2 inhibitory potency have been proposed to explain this increased risk of myocardial infarction (MI). Among NSAIDs, diclofenac appeared to be associated with a relatively higher risk of MI, similar to that of rofecoxib, compatible with the drug's high COX-2 inhibitory potency. Recent studies have resulted in further information being available. A study in the Danish healthcare system using active comparators found a slightly increased risk of MI in healthy persons. However, risk decreased with increasing baseline cardiovascular risk, to the point that in patients at high cardiovascular risk, there was no additional risk associated with diclofenac compared with paracetamol or other NSAIDs. The other major study, from the SOS project, studied several million persons in four countries in Europe, comparing the use of many NSAIDs with non-use. That study found a slightly increased risk with diclofenac compared with non-use, but this was not different from other NSAIDs. Comparing risks with selectivity or potency found no effect of either. These studies refute the main hypotheses to explain the coronary risk of NSAIDs. Finding risk in healthy low-risk patients only questions the reality of a link between the use of the drugs and the occurrence of MI in these conditions. Biases or confounding may be the major reason for small increases in cardiovascular risks in healthy users of NSAIDs in real life.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Diclofenaco/efeitos adversos , Cardiotoxicidade , Doenças Cardiovasculares/epidemiologia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Humanos , Lactonas/efeitos adversos , Metanálise como Assunto , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/epidemiologia , Fatores de Risco , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/epidemiologia , Sulfonas/efeitos adversos
20.
Environ Int ; 134: 105328, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778932

RESUMO

Bisphenol A (BPA) and its replacement analog, bisphenol S (BPS), have been proposed as environmental obesogen to disrupt the lipid metabolism through regulating peroxisome proliferator-activated receptor gamma (PPARγ) receptor. However, there is a dearth of information on whether this biological effect can occur in human macrophage, a cell type which closely interacts with adipocytes and hepatocytes to control lipid metabolism. Here, we for the first time investigate the activity of BPA and BPS on PPARγ pathway in human macrophages. The results demonstrated that BPA and BPS served as activators of PPARγ in human macrophage cell line, and significantly induced the expression of lipid metabolism-related genes, including fatty acid binding protein 4 (FABP4), cluster of differentiation 36 (CD36) and nuclear receptor subfamily 1 group H member 3 (NR1H3). In PPARγ knockout cells, expression of these genes was down-regulated, suggesting that these genes are dependent on PPARγ. The underlying mechanisms were further investigated using an in vivo mouse model, and the results confirmed the induction of PPARγ and its respective target genes in mice following exposure to BPA or BPS. Moreover, the observed alteration of PPARγ expression highly correlated with the disturbance of metabolism profiles in liver tissues as detected by 1H Nuclear Magnetic Resonance (NMR)-based metabonomics. Overall, this study provided the first evidence that BPA and BPS activated PPARγ and its target genes in human macrophages, and provided comprehensive information to confirm that BPA and BPS disturb the metabolism through targeting PPARγ via both in vitro assays and in vivo animal models.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Macrófagos/efeitos dos fármacos , PPAR gama/metabolismo , Fenóis/efeitos adversos , Sulfonas/efeitos adversos , Animais , Antígenos CD36 , Células Cultivadas , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado , Metabolômica , Camundongos
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