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1.
Int J Clin Pharmacol Ther ; 57(12): 596-602, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31599225

RESUMO

OBJECTIVES: To evaluate the pharmacokinetics of PC-SOD after single intravenous administration and its safety profile in healthy Chinese subjects. MATERIALS AND METHODS: This was a phase 1, randomized, double-blind, placebo-controlled, sequential, single-dose, and dose-escalation study. The study was done in 4 cohorts and a total of 40 subjects received a single dose of PC-SOD (from 20 to 160 mg). There were 12 subjects in each dose group (10 active treatments and 2 placebos), except a 20-mg group, in which all 4 subjects were given active treatment. Serial venous blood samples were collected up to 168 hours after dosing. Serum samples were analyzed using an enzyme-linked immunosorbent assay. Pharmacokinetic parameters of PC-SOD were calculated via noncompartmental analysis using the WinNonlin. RESULTS: After intravenous administration, PC-SOD reached the peak concentration quickly with a median tmax of 0.5 - 1.3 hours across all dose cohorts. After reaching Cmax, the mean T1/2 was 35.9 - 42.3 hours, which was independent of dose. The CL and Vz were 0.13 L/h and 6.72 L, 0.13 L/h and 7.33 L, and 0.11 L/h and 6.88 L for the 40, 80, and 160 mg dose cohorts, respectively. Over the dose range of 20 - 160 mg, the mean Cmax increased from 5,546.6 to 44,145.2 h×ng/mL and AUClast increased from 117,464.5 to 1,348,209.4 h×ng/mL. The 90% CI for ß of AUC or Cmax slightly exceeded the criterion, indicating that there was approximate dose proportionality over the range of 20 - 160 mg or 40 - 160 mg of PC-SOD. Generally, PC-SOD was well tolerated in doses up to 160 mg in healthy Chinese subjects. Reversible elevated blood triglyceride levels were reported in 2 subjects as moderate adverse events, and all other reported adverse events were considered to be mild. The possibility of a drug hypersensitivity syndrome was not high for PC-SOD in Chinese subjects based on current data. CONCLUSION: Single intravenous administrations of PC-SOD in doses up to 160 mg were well tolerated in healthy Chinese subjects. The prolonged half-life of PC-SOD was confirmed and independent of dose. Over the range of 20 - 160 mg, PC-SOD showed approximate dose proportionality. These findings suggest that it is worthwhile to investigate PC-SOD in clinical conditions characterized by a high radical overload.


Assuntos
Fosfatidilcolinas/farmacocinética , Superóxido Dismutase/farmacocinética , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Relação Dose-Resposta a Droga , Método Duplo-Cego , Meia-Vida , Humanos , Proteínas Recombinantes/farmacocinética
2.
Chem Pharm Bull (Tokyo) ; 67(9): 977-984, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474737

RESUMO

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1), an endogenous µ-opioid receptor ligand with strong antinociceptive activity, is not in clinical use because of its limited metabolic stability and membrane permeability. In this study, we develop a short-peptide self-delivery system for brain targets with the capability to deliver EM-1 without vehicle. Two amphiphilic EM-1 derivatives, C18-SS-EM1 and C18-CONH-EM1, were synthesized by attaching a stearyl moiety to EM-1 via a disulfide and amide bond, respectively. The amphiphilicity of EM-1 derivatives enabled self-assembling into nanoparticles for brain delivery. The study assessed morphology, circular dichroism, and metabolic stability of the formulations, as well as their pharmacodynamics and in vivo distribution, directly monitored by near-IR fluorescence imaging in mouse brains. In aqueous solution, the C18-SS-EM1 derivative self-assembled into spherical nanostructures with a diameter of 10-20 nm. Near-IR fluorescence analysis visualized the accumulation of the peptides in the brain. Importantly, the analgesic effect of C18-SS-EM1 nanoparticles was significantly stronger as compared to that of unmodified EM-1 or C18-CONH-EM1 nanoparticles. An in vitro release study demonstrated that self-assembled C18-SS-EM1 nanoparticles possessed reduction-responsive behavior. In summary, self-assembling C18-SS-EM1 nanoparticles, which integrate the advantages of lipidization, nanoscale characteristics and, labile disulfide bonds, represent a promising strategy for brain delivery of short peptides.


Assuntos
Encéfalo/metabolismo , Nanomedicina , Oligopeptídeos/farmacocinética , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/diagnóstico por imagem , Dicroísmo Circular , Portadores de Fármacos/química , Meia-Vida , Masculino , Camundongos , Nanopartículas/química , Oligopeptídeos/sangue , Oligopeptídeos/química , Espectroscopia de Luz Próxima ao Infravermelho
3.
Environ Monit Assess ; 191(9): 584, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31440848

RESUMO

A micro-liquid-liquid extraction (MLLE) technique coupled with liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis was established and validated to determine the residues of two macrocyclic lactone insecticides (spinetoram and spinosad) in green onion. The limit of quantification (LOQ) of the method, as demonstrated by the lowest acceptable recovery level, was 0.01 mg kg-1, and the obtained recoveries were 78.3-93.4% with relative standard deviations (RSDs) < 12.5%. The method was then applied for analyzing field samples collected after treatment with the tested insecticides under Egyptian open-field condition. The decline pattern, terminal residues, and dietary risk assessment of spinetoram and spinosad residues in green onion were evaluated for food safety. Spinetoram and spinosad residues' decline in green onion followed first-order kinetics with the half-lives of 1.2 and 1.42 days, respectively. Based on the results, the required period to reach their respective maximum residue limits (MRLs) was 1 and 0 days for spinetoram and spinosad residues in green onion, respectively, which indicates a short persistence level and high degradation rate. The results suggest that there is no unacceptable chronic or acute risk to human health from the consumption of green onion treated with spinetoram and spinosad according to the uses considered.


Assuntos
Inseticidas/análise , Macrolídeos/análise , Cebolas/química , Resíduos de Praguicidas/análise , Cromatografia Líquida/métodos , Combinação de Medicamentos , Egito , Monitoramento Ambiental , Meia-Vida , Lactonas , Microextração em Fase Líquida , Medição de Risco , Espectrometria de Massas em Tandem/métodos
4.
Lancet Haematol ; 6(10): e500-e509, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31420317

RESUMO

BACKGROUND: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. METHODS: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. FINDINGS: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2-10·6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0-3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events. INTERPRETATION: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism. FUNDING: Bayer AG, Janssen Research and Development.


Assuntos
Anticoagulantes/uso terapêutico , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Adolescente , Anemia/etiologia , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Peso Corporal , Criança , Pré-Escolar , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Fator Xa/análise , Feminino , Meia-Vida , Hemorragia/etiologia , Humanos , Lactente , Masculino , Neutropenia/etiologia , Tempo de Protrombina , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Resultado do Tratamento , Tromboembolia Venosa/patologia
5.
Chem Biol Interact ; 311: 108788, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31401088

RESUMO

Aqueous solutions of chlorpyrifos oxon are used to study the ability of chlorpyrifos oxon to catalyze protein crosslinking. Assays for protein crosslinking can avoid artifacts by using information on the stability of chlorpyrifos oxon in solution. We undertook to determine the half-life of chlorpyrifos oxon in aqueous solution because literature values do not exist. The rate of conversion of chlorpyrifos oxon to 3,5,6-trichloro-2-pyridinol was measured at 23 °C in 20 mM TrisCl pH 8 and pH 9 by recording loss of absorbance at 290 nm for chlorpyrifos oxon and increase in absorbance at 320 nm for 3,5,6-trichloro-2-pyridinol. The half-life of chlorpyrifos oxon was 20.9 days at pH 8 and 6.7 days at pH 9. Literature reports for the stability of other organophosphorus toxicants were summarized because our current studies suggest that other organophosphorus toxicants are also crosslinking agents.


Assuntos
Clorpirifos/análogos & derivados , Ésteres/química , Organofosfatos/química , Água/química , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Clorpirifos/química , Clorpirifos/metabolismo , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Organofosfatos/metabolismo , Hidróxido de Sódio/química , Espectrofotometria
6.
Ecotoxicol Environ Saf ; 183: 109489, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31394379

RESUMO

Avermectins and moxidectin are antiparasitics widely used as active pharmaceutical ingredients in veterinary medicine, as well as in pesticide formulations for pest control in agriculture. Although the use of these compounds provides benefits to agribusiness, they can impact the environment, since a large part of these substances may reach the soil and water from the excreta of treated animals and following direct applications to crops. The present work had the objective of evaluating the dissipation behaviors of abamectin, doramectin, eprinomectin, ivermectin, and moxidectin in four native Brazilian soils of different textural classes (clay, sandy-clay, sandy, and sandy-clay-loam), following OECD Guideline 307. The studies were conducted in a climate chamber at 22 °C, 71% relative humidity, and protected from light. The dissipation studies were carried out with all drugs together, since no difference was verified when studies were done with each drug separately. The concentrations of the drugs in the soils were determined using an ultra-high performance liquid chromatograph coupled to a fluorescence detector or a tandem mass spectrometer. The dissipation half-life (DT50) values ranged from 9 to 16 days and the calculated GUS index values were in the range from -1.10 to 0.08, indicating low mobility of the drugs in the soils evaluated and low tendency for leaching. In addition, a field study was carried out to evaluate the dissipation of abamectin after application of a foliar pesticide in an orange crop. A DT50 of 9 days was determined, which was similar to that obtained under controlled conditions in the climate chamber (12 days), indicating that biotransformation was the primary process influencing the overall dissipation.


Assuntos
Antiparasitários/química , Ivermectina/análogos & derivados , Macrolídeos/metabolismo , Praguicidas/química , Poluentes do Solo/química , Solo/química , Antiparasitários/análise , Brasil , Monitoramento Ambiental , Meia-Vida , Ivermectina/análise , Ivermectina/química , Ivermectina/metabolismo , Macrolídeos/análise , Macrolídeos/química , Praguicidas/análise , Poluentes do Solo/análise
7.
J Zoo Wildl Med ; 50(2): 322-329, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31260196

RESUMO

Flunixin meglumine, a nonsteroidal anti-inflammatory medication, has been used in rhinoceros species at doses extrapolated from domestic animals. There is increasing evidence to suggest significant variations exist in metabolism of drugs in exotic species. Due to the differences in drug metabolism, dose extrapolation from domestic animals may not be appropriate for exotic species. The objective of this study was to investigate the pharmacokinetics of flunixin meglumine in five white rhinoceroses (Ceratotherium simum) administered a single (1 mg/kg) oral dose of a commercial equine flunixin meglumine paste. Concentrations of flunixin and its metabolite 5-OH flunixin were analyzed, and pharmacokinetic parameters were estimated for each animal. Mean observed plasma concentrations peaked at 1,207 ± 601 ng/ml and occurred at 3 ± 1 hr. The geometric mean of the apparent elimination half-life after oral administration was 8.3 ± 1.2 hr. This data suggests that flunixin meglumine appears to be slowly metabolized or slowly absorbed in this species. No adverse clinical effects were observed during the study period. A single dose of 1 mg/kg appears safe for use in the white rhinoceros. Multidose studies are needed to determine if plasma accumulation of flunixin meglumine occurs and to evaluate safety.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Clonixina/análogos & derivados , Perissodáctilos/sangue , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Área Sob a Curva , Clonixina/administração & dosagem , Clonixina/sangue , Clonixina/farmacocinética , Feminino , Meia-Vida , Masculino
8.
Environ Monit Assess ; 191(8): 517, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31352622

RESUMO

The dissipation and residual levels of etoxazole and pyridaben in Goji berry under open field conditions were determined by using GC-NPD (gas chromatography with nitrogen and phosphorus detector) with modified QuEChERS method. At fortification levels of 0.01, 1, and 5 mg/kg in Goji berry, it was shown that recoveries were ranged from 80.40 to 100.9% with relative standard deviation of the method (RSD) for repeatability ranged from 2.20 to 4.25%. The limit of quantification (LOQ) of the method was 0.01 mg/kg. The dissipation rates of etoxazole and pyridaben were described by using first-order kinetics and its half-life, as they are 7.13 days, 5.77 days, and 5.99 days (etoxazole) and 1.02 day, 0.67 day, 1.02 day (pyridaben). The terminal residues of etoxazole and pyridaben were below the European maximum residue limit (MRL, 0.1 mg/kg) in Goji berry when measured 7 days after the final application, which suggested that the use of these insecticides was safe for humans. This study would help in providing the basic information for developing regulation to guard a safe use of etoxazole and pyridaben in Goji berry and prevent health problem from consumers.


Assuntos
Monitoramento Ambiental/métodos , Lycium/metabolismo , Oxazóis/análise , Resíduos de Praguicidas/análise , Piridazinas/análise , China , Meia-Vida , Humanos , Cinética , Lycium/crescimento & desenvolvimento , Oxazóis/metabolismo , Resíduos de Praguicidas/metabolismo , Piridazinas/metabolismo , Tibet
9.
Expert Opin Pharmacother ; 20(14): 1679-1687, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31335214

RESUMO

Introduction: A growth in the market for anti-diabetic drugs, along with an ever-increasing population suffering from type 2 diabetes mellitus (T2DM), requires a critical re-evaluation of anti-diabetic drugs used for a long time, in order to provide up-to-date practical prescribing information for clinicians. Alogliptin benzoate was firstly approved in 2010 in Japan for T2DM, both as a monotherapy or in combination with other anti-diabetic drugs. Areas covered: This article provides a comprehensive review of the latest data on alogliptin benzoate, including hypoglycemic activity and safety. Expert opinion: The cumulative evidence for alogliptin benzoate is robust with regards to glycemic efficacy and safety. Low hypoglycemia risks and weight changes support its consideration as a first-line medication for T2DM, either as a monotherapy or in combination therapy with other anti-diabetic drugs such as metformin. Ongoing trials will look to better analyze and address its safety and efficacy in pediatric patients and expand our clinical knowledge of this medication.


Assuntos
Benzoatos/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Piperidinas/uso terapêutico , Uracila/análogos & derivados , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada , Meia-Vida , Humanos , Hipoglicemia/patologia , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Uracila/efeitos adversos , Uracila/farmacocinética , Uracila/uso terapêutico
10.
Expert Opin Pharmacother ; 20(14): 1689-1702, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31339385

RESUMO

Introduction: The cyclooxygenase (COX)-2 inhibitor celecoxib is an approved compound for rheumatoid (RA) and osteoarthritis (OA), combining both anti-inflammatory and analgesic properties with a good gastrointestinal tolerability. Areas covered: This article covers the pharmacological properties and clinical efficacy as well as the latest safety data available for celecoxib with emphasis on the treatment of RA and OA. It is based primarily on a current literature search on PubMed and Web of Science, but also on the professional rheumatological expertise of the authors. Expert opinion: Celecoxib has been shown to be superior to placebo and equivalent to traditional non-steroidal anti-inflammatory drugs (tNSAIDs). Many studies have been published making celecoxib a good and safe treatment option in particular in moderate arthritis and patients without established cardiovascular (CV) disease. Moreover, older patients might gain significant benefits compared to tNSAIDs due to reduced gastrointestinal events even when having a history of ulcer bleedings. Nonetheless, there is still much to learn, especially regarding the prescription of celecoxib in patients with cardiovascular co-morbidities. While low doses seem to be safe according to present data, the knowledge on the more effective, higher doses >400 mg/day is still limited.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Celecoxib/uso terapêutico , Osteoartrite/tratamento farmacológico , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacocinética , Artrite Reumatoide/patologia , Doenças Cardiovasculares/etiologia , Celecoxib/efeitos adversos , Celecoxib/farmacocinética , Ensaios Clínicos como Assunto , Meia-Vida , Humanos , Osteoartrite/patologia , Prostaglandina-Endoperóxido Sintases/química , Prostaglandina-Endoperóxido Sintases/metabolismo , Resultado do Tratamento
11.
Expert Opin Pharmacother ; 20(14): 1755-1765, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31264486

RESUMO

Introduction: Antiseizure drugs (ASDs) play a central and crucial role in the treatment of epilepsy patients, as the majority require anticonvulsant treatment for an extended period of time. Since up to 30% of patients are refractory to medical treatment, new therapeutic options are necessary. Perampanel (PER) and brivaracetam (BRV) are the latest approved ASDs that may be considered in a variety of epilepsy syndromes. PER has a distinct and selective mode of action on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and is licensed for use in focal and generalized epilepsies. BRV is a derivative of levetiracetam but exhibits a 20-fold higher affinity and a faster brain entry time as a synaptic vesicle glycoprotein 2A (SV2A) ligand. Areas covered: This article reviews the advances in the epileptic treatment and provides a comparison of PER and BRV. Both drugs have shown comparable results in randomized controlled trials, and both are well tolerated. Expert opinion: PER and BRV have the potential to perform as important, broad-spectrum ASDs with significant market shares. BRV's intravenous formulation and fast penetration into the brain and PER's unique mode of action will result in the more frequent use of both drugs in status epilepticus.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Piridonas/uso terapêutico , Pirrolidinonas/uso terapêutico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Ensaios Clínicos como Assunto , Epilepsia/patologia , Meia-Vida , Humanos , Piridonas/efeitos adversos , Piridonas/farmacocinética , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Receptores de AMPA/química , Receptores de AMPA/metabolismo , Estado Epiléptico/tratamento farmacológico , Resultado do Tratamento
12.
Chem Biol Interact ; 308: 288-293, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150629

RESUMO

Hypaconitine is an active and highly toxic constituent derived from Aconitum species. Here we aimed to determine the chronotoxicity of hypaconitine in mice, and to investigate a potential role of metabolism in hypaconitine chronotoxicity. Cardiac toxicity was assessed by measuring CK (creatine kinase) and LDH (lactate dehydrogenase) levels after hypaconitine administration to wild-type and Bmal1-/- (a clock disrupted model) mice at different times of day. The mRNA and protein levels of Cyp3a11 in mouse livers were determined by qPCR and western blotting, respectively. In vitro metabolism was assessed using liver microsomes. Pharmacokinetic study of hypaconitine was performed with wild-type mice. We observed injection time-dependent toxicity (i.e., a more severe toxicity during the light phase than the dark phase) for hypaconitine in mice. The chronotoxicity was attributed to a difference in systemic exposure of hypaconitine caused by time of day-dependent metabolism. Furthermore, circadian metabolism of hypaconitine was accounted for by the diurnal expression of Cyp3a11, a major enzyme for hypaconitine detoxification in the liver. Moreover, Bmal1 ablation in mice abolished the daily rhythm of Cyp3a11 expression and abrogated the time-dependency of hypaconitine toxicity. In conclusion, circadian Cyp3a11 metabolism contributed to chronotoxicity of hypaconitine in mice. This metabolism-based chronotoxicity would facilitate the formulation of best timing for drug administration.


Assuntos
Aconitina/análogos & derivados , Relógios Circadianos , Citocromo P-450 CYP3A/metabolismo , Fígado/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Fatores de Transcrição ARNTL/deficiência , Fatores de Transcrição ARNTL/genética , Aconitina/metabolismo , Aconitina/farmacocinética , Aconitina/toxicidade , Animais , Creatina Quinase/sangue , Citocromo P-450 CYP3A/genética , Células HEK293 , Meia-Vida , Humanos , Fígado/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microssomos Hepáticos/metabolismo , RNA Mensageiro/metabolismo
13.
J Sci Food Agric ; 99(14): 6167-6172, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31226227

RESUMO

BACKGROUND: Grape is an important fruit consumed either fresh or processed, therefore, fungicide misuse of grape has become an issue of global food safety and human health. Pyraclostrobin, and cyazofamid have been applied to grape frequently. RESULTS: Here a simple QuEChERS (quick, easy, cheap, effective, rugged, and safe) liquid chromatography mass spectrometry technique has been developed and validated for the determination of pyraclostrobin, cyazofamid and its metabolite CCIM in open field grape samples. The recoveries of these three in the range of 0.01 to 5 mg kg-1 (n = 5) ranged from 73.1% to 97.9%. The relative standard deviations (RSDs) were below 12% for all cases. The limits of quantitation of each analyte was 0.005 mg kg-1 , which was lower than maximum residue limits of not only pyraclostrobin but also cyazofamid. Not only dissipation kinetics but also residue determination was obtained in grape for those three pesticides. Furthermore, their half-lives in grapes were 10.7-30.1 days, recommending the pre-harvest intervals for these three of 14 days. The calculated hazard quotient and acute hazard index lower than 100% illustrated the safety of intake of grape for the Chinese population for not only long-term but also short-term dietary risk assessment. CONSLUSIONS: The less than 30 day half-life illustrated that pyraclostrobin and cyazofamid could degrade relatively easily in the environment. The long-term and short-term dietary risk assessment also illustrated the intake safety of these three. Thus, a 14 day pre-harvest interval was safe and recommended. The results of this study contributed to environmental protection, food safety and human health. © 2019 Society of Chemical Industry.


Assuntos
Resíduos de Drogas/química , Fungicidas Industriais/química , Imidazóis/química , Estrobilurinas/química , Sulfonamidas/química , Vitis/química , China , Qualidade de Produtos para o Consumidor , Resíduos de Drogas/metabolismo , Contaminação de Alimentos/análise , Frutas/química , Fungicidas Industriais/metabolismo , Meia-Vida , Humanos , Imidazóis/metabolismo , Cinética , Medição de Risco , Estrobilurinas/metabolismo , Sulfonamidas/metabolismo , Espectrometria de Massas em Tandem , Vitis/metabolismo
14.
Food Chem ; 295: 58-63, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31174799

RESUMO

Control of residual levels of synthetic pyrethroids in fresh fruits and vegetables as well as in foodstuff made of fresh agricultural produces is of utmost importance. Apart from the need to more control on application of pesticides by farmers, simple and effective postharvest practices by consumers and/or manufacturers usually applied to produces before consumption may enhance food safety from potentially harmful pesticide residues. The present review discusses the underline factors that control the effectiveness of crops postharvest treatments and the possible mechanisms of loss of pesticides during food processing. It is shown that the effectiveness of postharvest processes is controlled by various factors and that understanding such factors is essential for more control of residual pesticides. Though postharvest processes may lead to substantial reduction of residual pesticides, metabolites of broken pesticides are of great concern.


Assuntos
Produtos Agrícolas , Contaminação de Alimentos/análise , Manipulação de Alimentos/métodos , Resíduos de Praguicidas/análise , Piretrinas/análise , Agricultura , Armazenamento de Alimentos/métodos , Frutas/química , Meia-Vida , Resíduos de Praguicidas/química , Piretrinas/química , Verduras/química
15.
Am J Vet Res ; 80(7): 702-708, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31246127

RESUMO

OBJECTIVE: To determine the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl metabolite (M-I) after IV administration of increasing doses of PTX to sheep. ANIMALS: 6 healthy adult Merino sheep. PROCEDURES: Each sheep received 10-, 20-, and 40-mg/kg doses of PTX, IV, with a 15-day washout period between doses. Blood samples were collected before and at predetermined times after administration of each dose to determine plasma PTX and M-I concentrations by high-performance liquid chromatography. Pharmacokinetic parameters for PTX and M-I were estimated by noncompartmental analysis. RESULTS: No adverse effects were observed after administration of the 10- and 20-mg/kg doses. Following administration of the 40-mg/kg dose, all sheep developed tachycardia and hypersalivation and appeared agitated for approximately 4 hours. Plasma PTX concentrations considered therapeutic in other species were achieved in all sheep after administration of all 3 doses. Pharmacokinetic parameters for PTX and M-I varied in a dose-dependent linear manner. For PTX, the mean area under the concentration-time curve (AUC), elimination half-life, and volume of distribution increased with dose and ranged from 15.67 to 94.66 h·µg/mL, 0.68 to 0.91 hours, and 0.55 to 0.66 L/kg, respectively, whereas clearance decreased with dose and ranged from 0.42 to 0.64 L/h/kg. The mean ratio of the AUC for M-I to AUC for PTX ranged from 0.38 to 0.46. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that pharmacokinetic parameters for PTX and M-I varied in a dose-dependent linear manner in healthy sheep. Further studies are warranted to determine the therapeutic threshold and optimal dosage for PTX in sheep.


Assuntos
Pentoxifilina/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Ovinos/metabolismo , Administração Intravenosa/veterinária , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão/veterinária , Estudos Cross-Over , Relação Dose-Resposta a Droga , Meia-Vida , Pentoxifilina/farmacocinética , Inibidores da Agregação de Plaquetas/farmacocinética , Distribuição Aleatória
16.
Chemistry ; 25(45): 10698-10709, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31149749

RESUMO

Two structurally constrained chelators based on a fused bicyclic scaffold, 4-amino-4-methylperhydro-pyrido[1,2-a][1,4]diazepin-N,N',N'-triacetic acids [(4R*,10aS*)-PIDAZTA (L1) and (4R*,10aR*)-PIDAZTA (L2)], were designed for the preparation of GaIII -based radiopharmaceuticals. The stereochemistry of the ligand scaffold has a deep impact on the properties of the complexes, with unexpected [Ga(L2)OH] species being superior in terms of both thermodynamic stability and inertness. This peculiar behavior was rationalized on the basis of molecular modeling and appears to be related to a better fit in size of GaIII into the cavity of L2. Fast and efficient formation of the GaIII chelates at room temperature was observed at pH values between 7 and 8, which enables 68 Ga radiolabeling under truly physiological conditions (pH 7.4).


Assuntos
Compostos Bicíclicos com Pontes/química , Quelantes/química , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , Teoria da Densidade Funcional , Radioisótopos de Gálio/química , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Cinética , Conformação Molecular , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Transferrina/química
17.
Chemotherapy ; 64(1): 17-21, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31167190

RESUMO

Prolonged intermittent renal replacement therapy (PIRRT) is an increasingly adopted method of renal replacement in critically ill patients. Like continuous renal replacement therapy, PIRRT can alter the pharmacokinetics (PK) of many drugs. In this setting, dosing data for antibiotics like benzylpenicillin are lacking. In order to enable clinicians to prescribe benzylpenicillin safely and effectively, knowledge of the effects of PIRRT on the plasma PK of benzylpenicillin is required. Herein, we describe the PK of benzylpenicillin in 2 critically ill patients on PIRRT for the treatment of penicillin-susceptible Staphylococcus aureus bacteremia complicated by infective endocarditis. Blood samples were taken for each patient taken over dosing periods during PIRRT and off PIRRT. Two-compartment PK models described significant differences in the mean clearance of benzylpenicillin with and without PIRRT (6.61 vs. 3.04 L/h respectively). We would suggest a benzylpenicillin dose of 1,800 mg (3 million units) every 6-h during PIRRT therapy as sufficient to attain PK/pharmacodynamic target.


Assuntos
Antibacterianos/farmacocinética , Penicilina G/farmacocinética , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/terapia , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacteriemia/complicações , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Penicilina G/farmacologia , Penicilina G/uso terapêutico , Terapia de Substituição Renal , Sepse/complicações , Sepse/diagnóstico , Sepse/tratamento farmacológico , Sepse/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificação , Resultado do Tratamento
18.
Anal Bioanal Chem ; 411(20): 5139-5148, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31179528

RESUMO

Therapeutic drug monitoring (TDM) is necessary in the clinical management of linezolid to improve its efficacy and reduce the risk of time- and dose-dependent toxicity. A novel and ultrahigh-throughput analytical method for the determination of linezolid in human plasma was developed based on direct analysis in real-time tandem mass spectrometry (DART-MS/MS) without chromatographic separation. After solid-phase extraction with Waters Oasis HLB, the linezolid and internal standard linezolid-d3 were detected by positive ion electrospray ionization followed by multiple reaction monitoring (MRM) of the transition at m/z 338.1 → 296.2 and 341.2 → 297.3, respectively. The use of DART-MS obviates the need for chromatographic separation and allowed determination of linezolid in a total run time of only 24 s per sample. The method was linear in the concentration range 0.20-25 µg mL-1 with intraday and interday precision <14.5% and accuracy ranging from -3.85% to 12.7%. The method was successfully applied to a pharmacokinetic study of linezolid in healthy male volunteers after oral administration of a 600 mg tablet. DART-MS/MS provides a rapid and sensitive method for the determination of linezolid that does not require chromatographic separation. It is eminently suitable to meet the high-throughput challenge of clinical TDM. Graphical abstract.


Assuntos
Antibacterianos/sangue , Linezolida/sangue , Espectrometria de Massas em Tandem/métodos , Antibacterianos/farmacocinética , Antibacterianos/normas , Área Sob a Curva , Meia-Vida , Humanos , Linezolida/farmacocinética , Linezolida/normas , Padrões de Referência , Reprodutibilidade dos Testes
19.
Carbohydr Polym ; 219: 39-45, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151539

RESUMO

An aqueous dispersion of alpha-lipoic acid (ALA) using octenylsuccinic anhydride-modified high-amylose starch (OS) was prepared, and thermal stability and cellular bioavailability of ALA were compared with those prepared using native high-amylose starch (HA) and beta-cyclodextrin (ß-CD). The ALA was homogeneously dispersed via the encapsulation of V-type amylose helices. In comparison with HA and ß-CD, OS exhibited a higher ALA absorption in Caco-2 cells, indicating the OS facilitated the intestinal epithelial transport of ALA. Oral administration of the encapsulated ALA in-vivo resulted in a higher maximum ALA plasma concentration and extended the terminal half-life by 30-40%. The area under the plasma concentration vs. time for the administration of ALA complexed by OS was 50% larger than that by HA, indicating the effectiveness of OS in enhancing the oral bioavailability of ALA. These results indicate that OS is an efficient carrier for ALA in oral delivery and bioavailability.


Assuntos
Amilose/química , Succinatos/química , Ácido Tióctico , Zea mays/química , beta-Ciclodextrinas/química , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Meia-Vida , Humanos , Masculino , Ratos Sprague-Dawley , Ácido Tióctico/sangue , Ácido Tióctico/farmacocinética
20.
N Z Vet J ; 67(5): 257-263, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31208293

RESUMO

Aim: To compare the pharmacokinetic profiles of tilmicosin, administered orally at a single dose of 20 mg/kg bodyweight, in healthy pigs and in pigs experimentally infected with Actinobacillus pleuropneumoniae. Methods: Twelve healthy crossbred pigs, aged approximately 8 weeks, were randomly assigned to uninfected and infected groups, with six pigs per group. Pigs in the infected group were inoculated intranasally with a bacterial suspension of A. pleuropneumoniae containing approximately 108 cfu. Each pig received a single oral dose of 20 mg/kg bodyweight of tilmicosin, given 3-4 hours after inoculation in infected pigs. Blood samples were collected before drug administration and up to 48 hours after tilmicosin administration. Concentrations of tilmicosin in plasma samples were determined by HPLC. Throughout the experimental period pigs were observed for signs of inappetence and clinical abnormalities. After sampling was complete pigs were subject to euthanasia and samples collected for gross and histopathology as well as microbiology. Results: Infected pigs showed signs of bradykinesia, nasal discharge dyspnoea, and coughing 1 hours after inoculation and A. pleuropneumoniae was cultured from the lungs of all infected pigs postmortem. Comparing pharmacokinetic parameters in uninfected and infected pigs, the maximum plasma concentration of tilmicosin was higher in uninfected pigs (1.17 (SD 0.17) vs. 0.96 (SD 0.17) µg/mL), the time to reach maximum concentration was shorter (1.53 (SD 0.23) vs. 2.40 (SD 0.37) hours), and the half-life of the absorption phase and half-life of the elimination phase were both shorter (0.66 (SD 0.08) vs. 1.00 (SD 0.27) hours) and (12.93 (SD 0.96) vs. 16.53 (SD 0.55) hours), respectively. The apparent volume of distribution was smaller in uninfected than infected pigs (1.91 (SD 0.22) vs. 2.16 (SD 0.21) L/kg). The relative bioavailability of tilmicosin in infected relative to uninfected pigs was 108.6 (SD 9.71)%. Conclusions and clinical relevance: The results of this study indicate that A. pleuropneumoniae infection significantly changed certain pharmacokinetic parameters of tilmicosin in pigs. In infected pigs tilmicosin exhibited a longer drug persistence and a better extent of absorption. These results indicate that it is necessary to monitor and adjust the dose of tilmicosin administration during the presence of pleuropneumonia. It is expected that this can optimise clinical efficacy and help avoid the development of resistance.


Assuntos
Infecções por Actinobacillus/veterinária , Actinobacillus pleuropneumoniae/efeitos dos fármacos , Antibacterianos/farmacocinética , Doenças dos Suínos/tratamento farmacológico , Tilosina/análogos & derivados , Infecções por Actinobacillus/tratamento farmacológico , Animais , Antibacterianos/sangue , Autopsia/veterinária , China , Cromatografia Líquida de Alta Pressão/veterinária , Modelos Animais de Doenças , Feminino , Meia-Vida , Pulmão/microbiologia , Masculino , Distribuição Aleatória , Suínos , Doenças dos Suínos/microbiologia , Tilosina/sangue , Tilosina/farmacocinética
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