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1.
Toxicol Lett ; 322: 32-38, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31923464

RESUMO

Neonicotinoids (NNs), a widely used class of systemic pesticides, are regarded as exhibiting selective toxicity in insects. However, NNs are suspected of exerting adverse effects on mammals as well, including humans. To date, only adult male animal models have been subjected to general toxicity studies of NNs; fetuses have yet to be considered in this context. Here, we focused on the NN clothianidin (CLO) for the first quantitative LC-MS/MS analysis of maternal-to-fetal transfer and residual property of once-daily (single or multiple days), orally administered CLO and its metabolites in mice. The results revealed the presence of CLO and its five metabolites at approximately the same respective blood levels in both dams and fetuses. In the dams, CLO showed a peak value 1 h after administration, after which levels rapidly decreased at 3 and 6 h. In the fetuses of each group, levels of CLO were almost the same as those observed in the corresponding dams. The present results clearly demonstrated rapid passage of CLO through the placental barrier. However, metabolite-dependent differences observed in blood pharmacokinetics and residual levels. This is the first quantitative demonstration of the presence of CLO and its metabolites in fetal mouse blood.


Assuntos
Sangue Fetal/metabolismo , Guanidinas/sangue , Inseticidas/sangue , Troca Materno-Fetal , Neonicotinoides/sangue , Tiazóis/sangue , Animais , Biotransformação , Feminino , Guanidinas/administração & dosagem , Guanidinas/farmacocinética , Guanidinas/toxicidade , Inseticidas/administração & dosagem , Inseticidas/farmacocinética , Inseticidas/toxicidade , Exposição Materna , Camundongos Endogâmicos ICR , Neonicotinoides/administração & dosagem , Neonicotinoides/farmacocinética , Neonicotinoides/toxicidade , Gravidez , Medição de Risco , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Tiazóis/toxicidade , Toxicocinética
2.
Int J Radiat Oncol Biol Phys ; 106(3): 564-570, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678634

RESUMO

PURPOSE: Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration-approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC. METHODS AND MATERIALS: This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design. RESULTS: Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans. CONCLUSIONS: The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted.


Assuntos
Cetuximab/administração & dosagem , Neoplasias de Cabeça e Pescoço/terapia , Radiossensibilizantes/administração & dosagem , Radioterapia de Intensidade Modulada , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Tiazóis/administração & dosagem , Adulto , Idoso , Quimiorradioterapia/métodos , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Serina-Treonina Quinases TOR/metabolismo , Tiazóis/efeitos adversos
3.
Cancer Sci ; 111(2): 429-440, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31808966

RESUMO

Soft tissue sarcomas (STSs) are a rare cancer type. Almost half are unresponsive to multi-pronged treatment and might therefore benefit from biologically targeted therapy. An emerging target is glycogen synthase kinase (GSK)3ß, which is implicated in various diseases including cancer. Here, we investigated the expression, activity and putative pathological role of GSK3ß in synovial sarcoma and fibrosarcoma, comprising the majority of STS that are encountered in orthopedics. Expression of the active form of GSK3ß (tyrosine 216-phosphorylated) was higher in synovial sarcoma (SYO-1, HS-SY-II, SW982) and in fibrosarcoma (HT1080) tumor cell lines than in untransformed fibroblast (NHDF) cells that are assumed to be the normal mesenchymal counterpart cells. Inhibition of GSK3ß activity by pharmacological agents (AR-A014418, SB-216763) or of its expression by RNA interference suppressed the proliferation of sarcoma cells and their invasion of collagen gel, as well as inducing their apoptosis. These effects were associated with G0/G1-phase cell cycle arrest and decreased expression of cyclin D1, cyclin-dependent kinase (CDK)4 and matrix metalloproteinase 2. Intraperitoneal injection of the GSK3ß inhibitors attenuated the growth of SYO-1 and HT1080 xenografts in athymic mice without obvious detrimental effects. It also mitigated cell proliferation and induced apoptosis in the tumors of mice. This study indicates that increased activity of GSK3ß in synovial sarcoma and fibrosarcoma sustains tumor proliferation and invasion through the cyclin D1/CDK4-mediated pathway and enhanced extracellular matrix degradation. Our results provide a biological basis for GSK3ß as a new and promising therapeutic target for these STS types.


Assuntos
Fibrossarcoma/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/metabolismo , Indóis/administração & dosagem , Maleimidas/administração & dosagem , Sarcoma Sinovial/tratamento farmacológico , Tiazóis/administração & dosagem , Ureia/análogos & derivados , Animais , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Fibrossarcoma/genética , Fibrossarcoma/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Indóis/farmacologia , Injeções Intraperitoneais , Maleimidas/farmacologia , Camundongos , Fosforilação/efeitos dos fármacos , Interferência de RNA , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Tiazóis/farmacologia , Regulação para Cima/efeitos dos fármacos , Ureia/administração & dosagem , Ureia/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Rev Med Suisse ; 15(674): 2232-2235, 2019 Dec 04.
Artigo em Francês | MEDLINE | ID: mdl-31804034

RESUMO

The use of direct oral anticoagulants (DOACs) has been largely -implemented in the management of venous thromboembolic disease in non-cancer patients. In cancer-associated thrombosis, low molecular weight heparins (LMWHs) and especially dalteparin have long been the reference standard therapy. Following the publication of two randomised trials comparing edoxaban and rivaroxaban to -dalteparin, DOACs now represent an alternative with an interesting efficacy and safety profile. Moreover, they offer the comfort of an oral administration and a lower cost. In patients with gastrointestinal or genitourinary cancers however, a higher bleeding risk has been shown with DOACs. LMWHs thus remain the treatment of choice in this group of patients.


Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Neoplasias/complicações , Tromboembolia Venosa/complicações , Tromboembolia Venosa/tratamento farmacológico , Administração Oral , Dalteparina/administração & dosagem , Dalteparina/uso terapêutico , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Rivaroxabana/administração & dosagem , Rivaroxabana/uso terapêutico , Tiazóis/administração & dosagem , Tiazóis/uso terapêutico
5.
BMC Neurol ; 19(1): 306, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783738

RESUMO

BACKGROUND: Treatment with anticoagulants, including direct oral anticoagulants (DOACs), should be considered for patients diagnosed with atrial fibrillation (AF) deemed at risk of ischaemic stroke. There are limited real world data related to the characteristics of patients with non-valvular AF who were not taking anticoagulants at the time of first ischaemic stroke and their subsequent DOAC treatment for the secondary prevention of stroke. Furthermore, little is known about patient adherence and experiences of DOAC treatment, especially for patients with non-valvular AF receiving DOAC therapy for the secondary prevention of stroke. METHODS: This is a UK mixed methodology, non-interventional study, involving retrospective and prospective medical record reviews and a prospective patient survey, in progress in six UK National Health Service secondary/tertiary care centres. The study comprises two groups of patients. Group 1 will include 300 eligible consenting patients with a first ischaemic stroke associated with non-valvular AF untreated with anticoagulants in the 12 months prior to stroke. Group 2 will include a subgroup of 150 patients from Group 1 initiated on one of the DOACs targeting activated Factor X (n = 50 on apixaban, n = 50 on edoxaban and n = 50 on rivaroxaban). The primary endpoint of the study is the CHA2DS2-VASc Risk Score prior to initiation of anticoagulation for patients included in Group 1. Secondary endpoints to be evaluated in Group 1 include patient demographics, clinical characteristics, relevant medical history, anticoagulant therapy initiated for secondary prevention of stroke, and relevant concomitant medication. Secondary endpoints to be evaluated in Group 2 include the time between stroke and DOAC initiation; prescribing of DOACs, other anticoagulants and concomitant medication; clinical assessments and hospital resource use; patient reported outcome measures, including the Morisky Medication Adherence Scale questionnaire and the Treatment Satisfaction Questionnaire for Medication. DISCUSSION: This mixed methodology study will provide new real world insights into the characteristics and management pathways and patient-reported experiences of this important group of patients. It is anticipated that the results of this study will provide the medical community and patients with important information to inform clinical decision-making and help facilitate meaningful improvements in the care of patients with non-valvular AF.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Isquemia Encefálica/etiologia , Acidente Vascular Cerebral/etiologia , Administração Oral , Humanos , Estudos Prospectivos , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Piridonas/administração & dosagem , Estudos Retrospectivos , Rivaroxabana/administração & dosagem , Tiazóis/administração & dosagem , Reino Unido
6.
Cutis ; 104(2): 94-96, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31603959

RESUMO

Methylisothiazolinone (MI) is a preservative commonly used in water-based personal care products. Increases in the allowable concentration of MI alone in these products has led to an epidemic of allergic contact dermatitis (ACD). Although personal care products are the most common source of MI contact allergy, other novel exposures include household products, industrial chemicals, paint, slime, and adhesive agents. Other isothiazolinones such as benzisothiazoline (BIT) and octylisothiazolinone (OIT) are uncommon in personal care products but have been found in leather products, glue, industrial chemicals, paints, and cleaning products. There may be cross-reactivity between OIT and MI, and a minority of patients who are allergic to MI are cosensitized to BIT. In this article, we review MI and related isothiazolinone chemicals.


Assuntos
Dermatite Alérgica de Contato/etiologia , Conservantes Farmacêuticos/efeitos adversos , Tiazóis/efeitos adversos , Cosméticos/efeitos adversos , Cosméticos/química , Reações Cruzadas , Humanos , Conservantes Farmacêuticos/administração & dosagem , Tiazóis/administração & dosagem
7.
Drugs ; 79(11): 1249-1253, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31256368

RESUMO

Alpelisib (Piqray™)-an orally available phosphatidylinositol 3-kinase (PI3K) inhibitor with specific activity against PI3K alpha (PI3Kα)-is being developed by Novartis for the treatment of breast cancer. Alpelisib has demonstrated efficacy in combination with fulvestrant as treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer in patients with a PIK3CA mutation and was recently approved for this indication in the USA. This article summarizes the milestones in the development of alpelisib leading to this first approval.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Tiazóis/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/genética , Aprovação de Drogas , Feminino , Fulvestranto/administração & dosagem , Humanos , Masculino , Mutação , Receptor ErbB-2/metabolismo , Estados Unidos , United States Food and Drug Administration
8.
Int J Mol Sci ; 20(13)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31266149

RESUMO

A decrease in heart rate (HR) is a well-established first-dose effect of sphingosine-1-phosphate subtype 1 receptor (S1P1R) modulators. For compounds with a short half-life (t1/2), this can be mitigated by gradual up-titration to therapeutic doses, whereas this is not required for compounds with a long t1/2 due to the less pronounced first-dose-related negative chronotropic effects. Based on this conceptual framework, this mechanistic study investigated whether first-dose HR effects of ponesimod (t1/2 ~32 h) can be mitigated by prior administration of cenerimod (t1/2 ~415 h). Healthy subjects (n = 12) were randomly assigned to active or placebo (2:1 ratio). Active treatment consisted of a single dose of 10 mg ponesimod on Day 1, 18, and 37 and multiple-dose administration of 2 mg once daily cenerimod (Day 9-36). Placebos of cenerimod and ponesimod were used as reference treatment. Cardiodynamic parameters were derived from 24 h Holter electrocardiogram (ECG) assessments on Day 1, 9, 10, 18, 36, and 37. Ponesimod (10 mg) alone triggered a transient mean decrease from baseline in hourly mean HR of 17 bpm. In contrast, decreases of 5.0 and 4.8 bpm were observed when ponesimod was given at near half steady-state (Day 18) or steady-state (Day 37) cenerimod, respectively. Hourly mean HR decreased after first administration of cenerimod and placebo was 7.4 and 4.0 bpm, respectively. Treatment with ponesimod and cenerimod alone or in combination was safe and tolerated. First-dose-related negative chronotropic effects of ponesimod were less pronounced when administered after initiation of cenerimod suggesting mitigation of this class-related liability.


Assuntos
Frequência Cardíaca/efeitos dos fármacos , /agonistas , Tiazóis/administração & dosagem , Adulto , Método Duplo-Cego , Eletrocardiografia Ambulatorial , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Contagem de Linfócitos , Masculino , Distribuição Aleatória , Tiazóis/farmacocinética , Adulto Jovem
9.
J UOEH ; 41(2): 211-216, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31292366

RESUMO

This report describes the case of a 67-year-old male with inflammatory breast cancer. He had noticed a left breast mass about seven years previously, but he had ignored it. He then visited our hospital 4 months previously when multiple small masses occurred in the left front chest wall. The tumor was diagnosed as skin metastasis of breast cancer by skin biopsy and he was referred to our department. The tumor cells were positive for estrogen receptor and progesterone receptor, and negative for HER2/neu, and the Ki67 expression was 10-15%. The subtype of his breast cancer was luminal A type. It had secondary inflammatory breast cancer and preceded chemotherapy. Also, as the veins in the lower extremity were filled with thrombus, we gave him an anticoagulant (Edoxaban), but due to the malignant hyper coagulable state (Trousseau syndrome) a CV port could not be implanted. 3 courses of docetaxel every 3 weeks failed to control the disease. Since an obstruction of the right iliac artery was newly observed, the anticoagulant was changed to cilostazol and rivaroxaban, but left second finger and fourth finger necrosis occurred due to peripheral circulatory failure. The condition of the disease was stabilized by FEC (5-FU, epirubicin, cyclophosphamide) therapy, but it became difficult to secure the blood vessel. Without constructing a CV port because of the thrombus, chemotherapy was changed to S-1 oral administration, and strength to the chest wall Modulated radiotherapy intensity modulated radiation therapy (IMRT) was performed. Although the tumor was reduced, the condition of the whole body gradually weakened and the patient died a year and a half after the start of the treatment. This case of inflammatory luminal in male breast cancer that caused thrombus was difficult to treat. Thrombosis in advanced cancer patients is often pointed out, but since male breast cancer patients tend to take a long time to visit the hospital after becoming aware of the mass and arrive at an advanced state, it is necessary to notify the public of the existence of male breast cancer.


Assuntos
Neoplasias da Mama Masculina/complicações , Neoplasias da Mama Masculina/terapia , Neoplasias Inflamatórias Mamárias/complicações , Neoplasias Inflamatórias Mamárias/terapia , Trombofilia/tratamento farmacológico , Trombofilia/etiologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama Masculina/patologia , Cilostazol/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Docetaxel/administração & dosagem , Combinação de Medicamentos , Epirubicina/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Evolução Fatal , Fluoruracila/administração & dosagem , Humanos , Neoplasias Inflamatórias Mamárias/patologia , Masculino , Ácido Oxônico/administração & dosagem , Piridinas/administração & dosagem , Radioterapia de Intensidade Modulada , Neoplasias Cutâneas/secundário , Síndrome , Tegafur/administração & dosagem , Tiazóis/administração & dosagem
10.
Int J Pharm ; 568: 118474, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31279055

RESUMO

Development of topically administered drug delivery systems for the treatment of ocular diseases have majorly focused on enhancing bioavailability of drugs in the ocular tissues. However, control of spatial distribution of topically administered drugs so as to restrict/avoid drug bioavailability at sensitive ocular tissues that are prone to drug induced adverse effects has not been explored. In this study, we aimed to reduce the bioavailability of topically administered corticosteroid, triamcinolone acetonide (TA) in lens via controlled spatial distribution in order to minimize TA induced posterior subcapsular cataract (PSC). For this, a negatively charged polymeric core-shell nanoparticulate drug delivery system composed of polycaprolactone (PCL) core and pluronic® F-68 (PF68) shell was fabricated. For in vivo studies, coumarin-6 (COU) loaded nanoparticles (NPs) were fabricated and studied for their biodistribution after topical administration in mice eyes and compared with free COU biodistribution. The administered COU loaded NPs differentially distributed in mice eyes and showed lower bioavailability in lens compared to free COU. Further, in vivo efficacy of the delivery system for its ability to minimize the rate of PSC progression was evaluated in diabetic rats. The results demonstrated that TA loaded PCL-PF68 NPs decreased PSC progression compared to free TA when administered topically.


Assuntos
Catarata/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Glucocorticoides/administração & dosagem , Triancinolona Acetonida/administração & dosagem , Administração Oftálmica , Animais , Disponibilidade Biológica , Caderinas/metabolismo , Catarata/induzido quimicamente , Catarata/metabolismo , Catarata/patologia , Cumarínicos/administração & dosagem , Cumarínicos/química , Cumarínicos/farmacocinética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Liberação Controlada de Fármacos , Olho/efeitos dos fármacos , Olho/metabolismo , Olho/patologia , Glucocorticoides/química , Masculino , Camundongos Endogâmicos C57BL , Poloxâmero/administração & dosagem , Poloxâmero/química , Poliésteres/administração & dosagem , Poliésteres/química , Ratos Sprague-Dawley , Tiazóis/administração & dosagem , Tiazóis/química , Tiazóis/farmacocinética , Triancinolona Acetonida/química
11.
J Dermatol ; 46(10): 911-913, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31342551

RESUMO

A 73-year-old healthy woman noticed black pigmentation on both thumbnails for 6 years. Upon her visit to our clinic, she had pigmented onychomycosis with onycholysis in the distal area. There was no evidence of paronychia. Direct microscopy using Zoomblue™ and histopathological examination showed aggregated blastoconidia. Fontana-Masson staining confirmed fungal melanin production. A combination of morphological features and genetic testing identified the isolates as Candida parapsilosis. Fungal melanonychia due to C. parapsilosis is rare, with only six cases reported since 1979. The minimum inhibitory concentration of the isolates was 0.25 µg/mL for itraconazole, less than 0.03 µg/mL for ravuconazole and 2.0 µg/mL for terbinafine. Both oral terbinafine treatment and itraconazole pulse therapy performed for 6 months were unsuccessful. The disease was ultimately cured with a 3-month treatment of oral fosravuconazole.


Assuntos
Candida parapsilosis/isolamento & purificação , Dermatoses da Mão/tratamento farmacológico , Melanose/tratamento farmacológico , Onicomicose/tratamento farmacológico , Tiazóis/administração & dosagem , Triazóis/administração & dosagem , Administração Oral , Idoso , Antifúngicos/administração & dosagem , Feminino , Dermatoses da Mão/diagnóstico , Dermatoses da Mão/microbiologia , Humanos , Melanose/diagnóstico , Melanose/microbiologia , Onicomicose/diagnóstico , Onicomicose/microbiologia , Pró-Fármacos/administração & dosagem , Resultado do Tratamento
12.
Int J Pharm ; 568: 118529, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31323368

RESUMO

Rapamycin as a novel macrolide immunosuppressive agent has been commonly used in organ transplantation owing to its stronger immunosuppressive effect, non-nephrotoxicity and lower side effect. However its drawbacks of low bioavailability and big individual difference remain to be improved in clinical application. Here rapamycin loaded TPGS-Lecithins-Zein nanoparticles (RTLZ-NPs) with core-shell structure were prepared by the phase separation method. The RTLZ-NPs were approximately 190.3 nm in size, with PDI and zeta potential about 0.256 and -19.71 mV respectively. Drug entrapment and loading achieved were about 86.64 and 25.73% respectively. Meanwhile RTLZ-NPs exhibited favorable enzymolysis resistance abilities in gastrointestinal environments and enhanced uptake in Caco-2 cells. The optimum absorption sites of rapamycin in the intestine were duodenum and jejunum as single-pass intestinal perfusion assay. Upon also considering the results of Caco-2 cell assay, it could be speculated that the transport of rapamycin in vivo involved active transport as well as P-glycoprotein (P-gp) based efflux. Finally, the relative oral bioavailability of RTLZ-NPS was 4.33 fold higher than free rapamycin in SD rat. Altogether the designed nanoparticles can be an efficient oral delivery strategy for rapamycin analogues to prevent the attacks from destructive enzymes, reduce cell efflux, increase cell uptake, and then enhance the oral bioavailability.


Assuntos
Portadores de Fármacos/administração & dosagem , Lecitinas/administração & dosagem , Nanopartículas/administração & dosagem , Sirolimo/administração & dosagem , Vitamina E/administração & dosagem , Zeína/administração & dosagem , Administração Oral , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/administração & dosagem , Cumarínicos/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Absorção Intestinal/efeitos dos fármacos , Lecitinas/química , Lecitinas/farmacocinética , Masculino , Nanopartículas/química , Ratos Sprague-Dawley , Sirolimo/química , Sirolimo/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/química , Vitamina E/química , Vitamina E/farmacocinética , Zeína/química , Zeína/farmacocinética
13.
Heart Vessels ; 34(12): 2011-2020, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31123819

RESUMO

The aims of this study were to determine the distribution of plasma concentration of edoxaban (PC-Ed) with their 90% interval (on therapy range) and its correlation with anticoagulation markers in patients with non-valvular atrial fibrillation (NVAF). Consecutive 97 NVAF patients under edoxaban therapy were evaluated (60/30 mg dose, n = 48/49; men/women, n = 71/26; age, 69 years). CHADS2 score 0, 1, and ≥ 2 were 27%, 44%, and 29%, respectively. The mean (90% interval) of PC-Ed by LC-MS/MS was 194.3 (49.4-345.3) and 17.0 (4.8-40.7) ng/mL at peak (2-4 h post-dose) and trough (pre-dose), respectively. Correlation of prothrombin time (PT) with PC-Ed was higher than that of activated partial thromboplastin time (aPTT). Among 6 PT reagents, Coagupia PT-N and Simplastin Excel S (both PT reagents) showed the highest predictive capability for the upper outlier of PC-Ed at peak and trough. Among 4 aPTT reagents, only Thrombocheck APTT measured at peak had a significant predictive capability. When using PT reagents, both peak and trough sampling showed a similar predictive capability for the upper outliers of PC-Ed with a high sensitivity, but a relatively low specificity. We demonstrated the distributions of plasma concentration, PT with 6 reagents, and aPTT with 4 reagents under edoxaban therapy in Japanese patients with NVAF, showing their 90% intervals. For predicting the upper outlier of PC-Ed, PT was more sensitive compared with aPTT, whereas predicting capability for the outliers of PC-Ed was mostly similar between peak and trough samplings among PT reagents (UMIN 000032492).


Assuntos
Fibrilação Atrial/sangue , Tempo de Tromboplastina Parcial/métodos , Tempo de Protrombina/métodos , Piridinas/farmacocinética , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/farmacocinética , Administração Oral , Idoso , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Feminino , Seguimentos , Humanos , Incidência , Japão/epidemiologia , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Piridinas/administração & dosagem , Curva ROC , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Tiazóis/administração & dosagem , Resultado do Tratamento
14.
Pest Manag Sci ; 75(12): 3363-3370, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074102

RESUMO

BACKGROUND: Two field experiments were conducted to determine the efficacy and field performance of three new non-fumigant chemical nematicides (fluensulfone, fluopyram, and fluazaindolizine) and two biological nematicides (Burkholderia rinojensis strain A396 and Purpureocillium lilacinus strain 251) for management of root-knot nematodes (Meloidogyne javanica) on tomato and associated double-crops in Florida. RESULTS: In experiment 1, soil fumigation with metam potassium increased plant growth and reduced root galling on tomato by 77% relative to that of the untreated soil. All non-fumigant chemical nematicides reduced root galling on tomato (47-85% reduction); however, only fluensulfone showed a trend towards yield enhancement. In experiment 2, soil fumigation with chloropicrin increased plant growth and reduced root galling on tomato by 35% relative to that of the untreated soil; however, end-of-season populations of M. javanica in soil were larger than that of the non-fumigated soil. Fluensulfone showed a trend towards reduced root galling and enhanced fruit yield, whereas other non-fumigant nematicides did not. Double-cropped cucumber was 69% more galled when planted into soil previously fumigated with chloropicrin relative to that of untreated soil, and also showed reduced plant vigor and fruit yield. CONCLUSION: Fluensulfone shows significant potential to be a component of an integrated pest management strategy for tomato in Florida. © 2019 Society of Chemical Industry.


Assuntos
Antinematódeos/administração & dosagem , Ascomicetos/fisiologia , Burkholderia/fisiologia , Lycopersicon esculentum/crescimento & desenvolvimento , Controle Biológico de Vetores/métodos , Doenças das Plantas/prevenção & controle , Tylenchoidea , Animais , Benzamidas/administração & dosagem , Produção Agrícola/métodos , Proteção de Cultivos/métodos , Cucumis sativus/crescimento & desenvolvimento , Florida , Compostos Heterocíclicos com 2 Anéis/administração & dosagem , Lycopersicon esculentum/parasitologia , Doenças das Plantas/parasitologia , Piridinas/administração & dosagem , Sulfonamidas/administração & dosagem , Sulfonas/administração & dosagem , Tiazóis/administração & dosagem
15.
AAPS PharmSciTech ; 20(5): 182, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31054050

RESUMO

A feasibility evaluation of the addition of fumed silica (SiO2) into an agitated dryer to aid spray-dried solid dispersion intermediate (SDSDi) flow during secondary drying and discharge is described. The quantity of SiO2 to enhance the flow character of SDSDi was assessed by measuring particle size distribution, bulk density, and flow-through-an-orifice. Results indicate that the addition of the SiO2 did not alter the drying kinetics and did not impact the bulk particle size distribution of the SDSDi. While bulk density of SDSDi increased with the addition of SiO2, the flow, and thus the recovery of the SDSDi-SiO2 batch from the secondary dryer, was significantly higher than that for the intermediate alone. Imaging indicated uniform distribution of SiO2 in the bulk powder and coating on intermediate particles. Premixing and co-sieving of the SiO2 with a portion of pre-dry SDSDi promotes the uniform distribution of SiO2 within the bulk powder bed.


Assuntos
Coloides , Dióxido de Silício/química , Dessecação , Estudos de Viabilidade , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Tamanho da Partícula , Pós , Pirrolidinas/administração & dosagem , Tecnologia Farmacêutica , Tiazóis/administração & dosagem
16.
Acta Trop ; 196: 42-47, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077641

RESUMO

Over the past decade, insecticide resistance to malaria vectors has been identified in 71 malaria endemic countries. This has posed a major global health challenge in the fight against malaria, with declining rates of indoor residual spraying coverage attributed to pyrethroid-resistance. As part of its vector control monitoring strategies, the Bioko Island Malaria Control Project (BIMCP) in Equatorial Guinea conducted routine insecticide resistance bioassays using the WHO's standard susceptibility tests from 2013 to 2018. During the same period, the frequency of the target-site knockdown resistance allele (kdr) in the local vector population was also determined via PCR for detection of the L1014 F mutation. Biochemical analysis for metabolic resistance was also conducted in 2015. From 2016-2017, Fludora™ fusion, a formulated combination of clothianidin (a neonicotinoid) and deltamethrin (a pyrethroid) was evaluated for 9 months on Bioko Island, using the WHO's standard test procedure for determining residual effectiveness of insecticides on sprayed surfaces. In 2016, the mortality rate of the vectors on 0.05% deltamethrin was as low as 38%. The frequency of the West African form of knockdown resistance allele, L1014 F, in the vector population was as high as 80%, and metabolic resistance analysis indicated high upregulated cytochrome P450 s. However, the residual effectiveness of Fludora™ fusion recorded mortalities above 80% after 72 h of exposure for 8 months. Although both target-site knockdown resistance and metabolic resistance to pyrethroids were implicated in the local malaria vector population, Fludora™ fusion was effective under field conditions in controlling the resistant vectors for a period of 8 months on wooden surfaces on Bioko Island and represents a valuable addition to IRS programs, especially in regions with high levels of pyrethroid resistance.


Assuntos
Anopheles/efeitos dos fármacos , Guanidinas/farmacologia , Controle de Mosquitos/métodos , Mosquitos Vetores/efeitos dos fármacos , Neonicotinoides/farmacologia , Nitrilos/farmacologia , Piretrinas/farmacologia , Tiazóis/farmacologia , Animais , Guiné Equatorial/epidemiologia , Guanidinas/administração & dosagem , Guanidinas/química , Humanos , Resistência a Inseticidas/genética , Inseticidas/administração & dosagem , Inseticidas/química , Inseticidas/farmacologia , Ilhas , Malária/epidemiologia , Malária/prevenção & controle , Neonicotinoides/administração & dosagem , Neonicotinoides/química , Nitrilos/administração & dosagem , Nitrilos/química , Piretrinas/administração & dosagem , Piretrinas/química , Tiazóis/administração & dosagem , Tiazóis/química
17.
Org Biomol Chem ; 17(21): 5305-5315, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31094391

RESUMO

Numerous studies demonstrate the promise of opioid peptides as analgesics, but poor oral bioavailability has limited their therapeutic development. This study sought to increase the oral bioavailability of opioid peptides by cyclization, using Hantzsch-based macrocyclization strategies to produce two new series of cyclized DAMGO and Leu/Met-enkephalin analogs. Opioid receptor affinity and selectivity for compounds in each series were assessed in vitro with radioligand competition binding assays. Compounds demonstrated modest affinity but high selectivity for the mu, delta, and kappa opioid receptors (MOR, DOR and KOR), while selectivity for mu opioid receptors varied by structure. Antinociceptive activity of each compound was initially screened in vivo following intracerebroventricular (i.c.v.) administration and testing in the mouse 55 °C warm-water tail-withdrawal test. The four most active compounds were then evaluated for dose- and time-dependent antinociception, and opioid receptor selectivity in vivo. Cyclic compounds 1924-10, 1936-1, 1936-7, and 1936-9 produced robust and long- lasting antinociception with ED50 values ranging from 0.32-0.75 nmol following i.c.v. administration mediated primarily by mu- and delta-opioid receptor agonism. Compounds 1924-10, 1936-1 and 1936-9 further displayed significant time-dependent antinociception after oral (10 mg kg-1, p.o.) administration. A higher oral dose (30 mg kg-1. p.o.) of all four cyclic peptides also reduced centrally-mediated respiration, suggesting successful penitration into the CNS. Overall, these data suggest cyclized opioid peptides synthesized by a Hantzsch-based macrocyclization strategy can retain opioid agonist activity to produce potent antinociception in vivo while conveying improved bioavailability following oral administration.


Assuntos
Analgésicos Opioides/farmacologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Encefalina Metionina/farmacologia , Receptores Opioides/agonistas , Tiazóis/farmacologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/química , Animais , Ciclização , Relação Dose-Resposta a Droga , Ala(2)-MePhe(4)-Gly(5)-Encefalina/administração & dosagem , Ala(2)-MePhe(4)-Gly(5)-Encefalina/química , Encefalina Metionina/administração & dosagem , Encefalina Metionina/química , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Taxa Respiratória , Tiazóis/administração & dosagem , Tiazóis/química
18.
Urol Int ; 103(2): 195-201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31096260

RESUMO

AIMS: To determine factors for treatment persistence in a real-life cohort of adult neurogenic lower urinary tract dysfunction. METHODS: We reviewed records of patients with neurogenic lower urinary tract dysfunction and mirabegron prescriptions. Exclusion criteria were indwelling urethral or suprapubic catheters and implanted neurostimulators. We extracted demographic data, indication for prescription, concomitant use of other agents with possible anticholinergic effect, beta blockers, duration of treatment and reason of discontinuation. RESULTS: We included 110 subjects in this study. Neurologic diagnoses included multiple sclerosis, Parkinson's disease, and other diagnoses (dementia, paraplegia, and tetraplegia). Previous usage of antimuscarinics was found in 78 patients (71%). Mirabegron was combined with antimuscarinics in 15 patients (14%). Drugs with any anticholinergic activity were taken by 94 subjects (86%). Mirabegron was taken for a median of 497 days and 60 patients discontinued the medication within the study period. Main reasons of discontinuation were lack of effect (44/110), side effects (10/110), and non-reimbursement (6/110). There were no differences in mirabegron discontinuation by neurological disease, beta blocker usage, or anticholinergic burden. CONCLUSIONS: Mirabegron is continued in more than half of patients with neurogenic lower urinary tract dysfunction for more than 6 months. Further research is needed to identify eventual predictive factors.


Assuntos
Acetanilidas/uso terapêutico , Tiazóis/uso terapêutico , Bexiga Urinaria Neurogênica/tratamento farmacológico , Agentes Urológicos/uso terapêutico , Acetanilidas/administração & dosagem , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tiazóis/administração & dosagem , Agentes Urológicos/administração & dosagem
19.
Rev Assoc Med Bras (1992) ; 65(4): 487-492, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31066800

RESUMO

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.


Assuntos
Acetanilidas/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Tiazóis/administração & dosagem , Bexiga Urinária Hiperativa/tratamento farmacológico , Antidepressivos/administração & dosagem , Benzilatos/administração & dosagem , Benzofuranos/administração & dosagem , Brasil , Tomada de Decisão Clínica , Quimioterapia Combinada , Humanos , Ácidos Mandélicos/administração & dosagem , Nortropanos/administração & dosagem , Pirrolidinas/administração & dosagem , Succinato de Solifenacina/administração & dosagem , Tartarato de Tolterodina/administração & dosagem
20.
Artigo em Inglês | MEDLINE | ID: mdl-31055069

RESUMO

Sea-Nine™ 211 is an emerging biocide that has an adverse impact on aquatic environments. In this study, the marine polychaete Perinereis aibuhitensis was exposed to Sea-Nine (0.1, 1, and 10 µg L-1), and acute toxicity and biochemical responses such as changes in the intracellular contents of malondialdehyde (MDA) and glutathione (GSH) and enzymatic activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), and acetylcholinesterase (AChE) were evaluated over a period of 14 d. Determined median lethal doses, LC50 were 268 µg L-1, 142 µg L-1, and 55 µg L-1 at 24 h, 96 h, and 14 d, respectively. The MDA content increased significantly in a dose- and time-dependent manner, indicative of lipid peroxidation-related oxidative damage. Significantly higher intracellular GSH levels and antioxidant defense-related enzyme (CAT, SOD, GPx, GR, and GST) activities were observed after exposure to 10 µg L-1 Sea-Nine. In contrast, Sea-Nine treatment significantly reduced AChE activity at the highest concentration of Sea-Nine used (10 µg L-1). Taken together, these results indicate that sublethal concentrations of Sea-Nine are toxic to marine polychaetes through potential lipid peroxidation, induction of oxidative stress, and modulation of the cholinergic system. Our results can contribute to biomonitoring of aquatic environments and ecotoxicological research through the measurements of polychaete cellular defenses against waterborne biocides.


Assuntos
Desinfetantes/toxicidade , Poliquetos/efeitos dos fármacos , Tiazóis/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Antioxidantes/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Glutationa/metabolismo , Malondialdeído/metabolismo , Tiazóis/administração & dosagem , Poluentes Químicos da Água/administração & dosagem
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