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1.
J Agric Food Chem ; 68(6): 1563-1570, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927998

RESUMO

Ethanamizuril(N-{4-[4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-phenoxy]-phenyl}-acetamide, EZL) is a new anticoccidiosis compound and belongs to the class of triazines. In this study, the metabolism, distribution, and excretion of EZL were evaluated in chickens after administration of EZL at a single dosage. According to the relevant drug biotransformation rules, the exact molecular mass detection, the fragmentation characteristics, and the retention times, a total of five metabolites were identified in vivo in chickens, including two phase I metabolites and three phase II conjugated metabolites. The major metabolic pathways of EZL in chickens were deacetylation, hydroxylation, and glucuronidation. Regarding 14C-tissue residues after administration, kidney was considered to be the target tissue, as 14C-tissue residues could be detected at 240 h postdose. DeacetylEZL (M3) was the main metabolite, accounting for 68.65% and 25.62% of 14C in kidney at 6 and 24 h, respectively. In heart, muscle, skin+fat, and lung tissues, EZL was the main radioactive substance accounting for 94.88%, 97.32%, 96.23%, and 91.3% of 14C, respectively. In the liver, EZL and M3 were 20.76% and 54.65% of 14C, respectively. In chicken tissues the ratio of M5 was too low to be quantitated and it was mainly detected in chicken fecal and bile samples. In chicken excreta, EZL, M3, and glucuronidation of EZL (M5) accounted for 7.02%, 12.33%, and 10.32% of the dose, respectively and were eliminated primarily. This study presents the first detection of EZL metabolites, which is helpful for further understanding of the metabolic mechanism and in vivo intermediate processes of EZL. The results of this study will be good bases for better understanding EZL's anticoccidiosis mechanism and will serve as a helpful reference for assessing the risks to animals and humans.


Assuntos
Coccidiostáticos/farmacocinética , Triazinas/farmacocinética , Animais , Biotransformação , Galinhas , Coccidiostáticos/administração & dosagem , Coccidiostáticos/metabolismo , Hidroxilação , Rim/química , Rim/metabolismo , Fígado/química , Fígado/metabolismo , Pulmão/química , Pulmão/metabolismo , Músculos/química , Músculos/metabolismo , Triazinas/administração & dosagem , Triazinas/metabolismo
2.
Cancer Sci ; 111(2): 536-547, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31778267

RESUMO

Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).


Assuntos
Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Triazinas/administração & dosagem , Idoso , Cápsulas , Relação Dose-Resposta a Droga , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Comprimidos , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/farmacocinética
3.
Toxicol Lett ; 318: 50-56, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31622650

RESUMO

The development of three generic multi-compartment physiologically based kinetic (PBK) models is described for farm animal species, i.e. cattle, sheep, and swine. The PBK models allow one to quantitatively link external dose and internal dose for risk assessment of chemicals relevant to food and feed safety. Model performance is illustrated by predicting tissue concentrations of melamine and oxytetracycline and validated through comparison with measured data. Overall, model predictions were reliable with 71% of predictions within a 3-fold of the measured data for all three species and only 6% of predictions were outside a 10-fold of the measured data. Predictions within a 3-fold change were best for cattle, followed by sheep, and swine (82%, 76%, and 63%). Global sensitivity analysis was performed to identify the most sensitive parameters in the PBK model. The sensitivity analysis showed that body weight and cardiac output were the most sensitive parameters. Since interspecies differences in metabolism impact on the fate of a wide range of chemicals, a key step forward is the introduction of species-specific information on transporters and metabolism including expression and activities.


Assuntos
Ração Animal , Gado/metabolismo , Modelos Biológicos , Oxitetraciclina/farmacocinética , Triazinas/farmacocinética , Ração Animal/toxicidade , Animais , Bovinos , Oxitetraciclina/administração & dosagem , Oxitetraciclina/efeitos adversos , Reprodutibilidade dos Testes , Carneiro Doméstico , Especificidade da Espécie , Sus scrofa , Distribuição Tecidual , Triazinas/administração & dosagem , Triazinas/toxicidade
4.
Parasit Vectors ; 12(1): 592, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852494

RESUMO

BACKGROUND: Eimeria tenella is a highly pathogenic coccidian that causes avian coccidiosis. Both nitromezuril (NZL) and ethanamizuril (EZL) are novel triazine compounds with high anticoccidial activity, but the mechanisms of their action are still unclear. This study explored the response of E. tenella to NZL and EZL by the study of changes in protein composition of the second-generation merozoites. METHODS: Label-free quantification (LFQ) proteomics of the second-generation merozoites of E. tenella following NZL and EZL treatment were studied by LC-MS/MS to explore the mechanisms of action. The identified proteins were annotated and analyzed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and protein-protein interaction (PPI) networks analysis. RESULTS: A total of 1430 proteins were identified by LC-MS/MS, of which 375 were considered as differential proteins in response to drug treatment (DPs). There were 26 only found in the NZL treatment group (N-group), 63 exclusive to the EZL treatment group (E-group), and 80 proteins were present in both drug groups. In addition, among the DPs, the abundant proteins with significantly altered expression in response to drug treatment (SDPs) were found compared with the C-group, of which 49 were upregulated and 51 were downregulated in the N-group, and 66 upregulated and 79 downregulated in the E-group. Many upregulated proteins after drug treatment were involved in transcription and protein metabolism, and surface antigen proteins (SAGs) were among the largest proportion of the downregulated SDPs. Results showed the top two enriched GO terms and the top one enriched pathway treated with EZL and NZL were related, which indicated that these two compounds had similar modes of action. CONCLUSIONS: LFQ proteomic analysis is a feasible method for screening drug-related proteins. Drug treatment affected transcription and protein metabolism, and SAGs were also affected significantly. This study provided new insights into the effects of triazine anticoccidials against E. tenella.


Assuntos
Coccidiose/veterinária , Coccidiostáticos/administração & dosagem , Eimeria tenella/crescimento & desenvolvimento , Merozoítos/efeitos dos fármacos , Doenças das Aves Domésticas/tratamento farmacológico , Proteínas de Protozoários/química , Triazinas/administração & dosagem , Animais , Galinhas , Coccidiose/tratamento farmacológico , Coccidiose/parasitologia , Eimeria tenella/efeitos dos fármacos , Eimeria tenella/genética , Eimeria tenella/metabolismo , Merozoítos/genética , Merozoítos/crescimento & desenvolvimento , Merozoítos/metabolismo , Doenças das Aves Domésticas/parasitologia , Proteômica , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Espectrometria de Massas em Tandem
5.
PLoS One ; 14(5): e0217307, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31107922

RESUMO

Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , Administração Oral , Animais , Antivirais/administração & dosagem , Modelos Animais de Doenças , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Feminino , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunocompetência , Hospedeiro Imunocomprometido , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/fisiologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/fisiologia , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Influenza Humana/virologia , Camundongos , Camundongos Endogâmicos BALB C , Orthomyxoviridae/fisiologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Oseltamivir/farmacologia , Oxazinas/administração & dosagem , Piridinas/administração & dosagem , Tiepinas/administração & dosagem , Triazinas/administração & dosagem , Replicação Viral/efeitos dos fármacos
6.
Parasit Vectors ; 12(1): 272, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138327

RESUMO

BACKGROUND: Toltrazuril is frequently administered for the metaphylactic control of piglet cystoisosporosis. In a previous study, the efficacy of parenteral toltrazuril (45 mg/piglet, Group Forceris®) applied on the 2nd day of life (dol), and of oral toltrazuril (20 mg/kg of body weight, Group Baycox®) applied on the 4th dol was evaluated in an experimental model with Cystoisospora suis infection on the 3rd dol (late infection, LI). In a follow-up study, efficacy and safety were evaluated against infections with C. suis on the 1st dol (early infection, EI). Parameters included oocyst excretion and faecal consistency, body weight development, bacteriological examinations and animal health. RESULTS: All control piglets (n = 12) shed oocysts and had diarrhoea, while parasite excretion was completely suppressed in both treatment groups (n = 13 each) and diarrhoea was reduced to a single animal (Forceris® group), resulting in significant differences for these parameters between the treated groups and the controls without significant differences among the treatment groups. No treatment-related adverse events were noted. Body weight gain was reduced in the control group during the acute phase of infection, resulting in significantly lower body weight on the 15th dol. Sows and piglets shed high numbers of Escherichia coli. Clostridium perfringens type A was only detected in low amounts in pooled litter samples. In comparison to the LI study oocyst shedding was more intense in the control animals in EI, while diarrhea was more frequent in LI. In both infection models a high efficacy of toltrazuril in the control of parasitological and clinical outcomes of experimental C. suis infection could be demonstrated. Since in the LI study high numbers of Cl. perfringens type A were detected, it is hypothesized that colonization with these opportunistic pathogens has synergistic effects with C. suis and may explain variable clinical outcomes in untreated animals as well as the sporadic occurrence of diarrhea in toltrazuril-treated piglets. CONCLUSIONS: Parenteral and oral toltrazuril administered on the 2nd or 4th dol is safe and effective against experimental infections with C. suis on the 1st to 3rd dol. The clinical outcome of experimental infections seems influenced by bacterial coinfections.


Assuntos
Coccidiose/veterinária , Ferro/uso terapêutico , Sarcocystidae/efeitos dos fármacos , Doenças dos Suínos/tratamento farmacológico , Triazinas/uso terapêutico , Administração Oral , Animais , Animais Lactentes , Bactérias/isolamento & purificação , Peso Corporal/efeitos dos fármacos , Coccidiose/tratamento farmacológico , Coinfecção , Modelos Animais de Doenças , Combinação de Medicamentos , Fezes/parasitologia , Feminino , Seguimentos , Injeções Intramusculares , Ferro/administração & dosagem , Oocistos/efeitos dos fármacos , Oocistos/isolamento & purificação , Distribuição Aleatória , Suínos , Doenças dos Suínos/parasitologia , Resultado do Tratamento , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Ganho de Peso
7.
PLoS Negl Trop Dis ; 13(3): e0007175, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30901321

RESUMO

BACKGROUND: Globally, working equines have a continued and growing socioeconomic role in supporting the livelihoods of between 300-600 million people in low income countries which is rarely recognised at a national or international level. Infectious diseases have significant impact on welfare and productivity in this population and equine trypanosomiasis is a priority disease due to its severity and prevalence. Strategies are required to improve the prevention, diagnosis, management and treatment of trypanosomiasis in equines and more data are required on the efficacy and safety of current trypanocidal drugs. METHODS: A prospective randomised, open-label non-inferiority trial was performed in The Gambia on horses and donkeys that fulfilled 2/5 clinical inclusion criteria (anaemia, poor body condition, pyrexia, history of abortion, oedema). Following randomised trypanocidal treatment (diminazene diaceturate, melarsomine dihydrochloride or isometamidium chloride), animals were observed for immediate adverse drug reactions and follow-up assessment was performed at 1 and 2 weeks. Blood samples underwent PCR analysis with specific Trypanosoma sp. primers. Treatment efficacy was assessed by measuring changes in clinical parameters, clinicopathological results and PCR-status post-treatment after evaluating for bias. Using PCR status as the outcome variable, non-inferiority of isometamidium treatment was determined if the upper bound limit of a 2-sided 95% CI was less than 10%. RESULTS: There was a significant beneficial effect upon the Trypanosoma sp. PCR positive population following trypanocidal treatment for all groups. The findings of clinical evaluation and PCR status supported a superior treatment effect for isometamidium. Melarsomine dihydrochloride efficacy was inferior to isometamidium. There were immediate, self-limiting side effects to isometamidium in donkeys (26%). Diminazene had the longest duration of action as judged by PCR status. CONCLUSIONS: The data support the continued use of isometamidium following careful dose titration in donkeys and diminazene for trypanosomiasis in equines using the doses and routes of administration reported.


Assuntos
Diminazena/análogos & derivados , Equidae/parasitologia , Doenças dos Cavalos/tratamento farmacológico , Fenantridinas/administração & dosagem , Tripanossomicidas/administração & dosagem , Trypanosoma/efeitos dos fármacos , Tripanossomíase/veterinária , Animais , Arsenicais/administração & dosagem , Arsenicais/efeitos adversos , Diminazena/administração & dosagem , Diminazena/efeitos adversos , Feminino , Gâmbia/epidemiologia , Doenças dos Cavalos/epidemiologia , Doenças dos Cavalos/parasitologia , Cavalos , Masculino , Fenantridinas/efeitos adversos , Estudos Prospectivos , Distribuição Aleatória , Resultado do Tratamento , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Tripanossomicidas/efeitos adversos , Tripanossomíase/tratamento farmacológico , Tripanossomíase/epidemiologia , Tripanossomíase/parasitologia
8.
Pharmacology ; 103(5-6): 273-281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799431

RESUMO

This study aims at synthesizing novel di-morpholine 1,3,5-triazine derivatives as antidiabetic agent via inhibition of dipeptidyl peptidase-4 (DPP-4). The molecules were developed via sequential nucleophilic reaction to afford target derivatives 5(a-f) and subsequently tested for inhibitory potency against DPP iso-enzymes, such as DPP-4, DPP-8, and DPP-9. The in vitro inhibition assay suggested that these derivatives prominently and selectively inhibit DPP-4 over -DPP-8 and DPP-9. These molecules also showed no presence of cardiotoxicity, as confirmed by no activity against human Ether-à-go-go related gene channel. The study disclosed compound 5c as the most potent inhibitor of DPP-4 with IC50 of 1.10 nmol/L as compared to the standard. Compound 5c was further evaluated for oral glucose tolerance test (OGTT) and antidiabetic activity in ICR mice and Wistar rats, respectively. In OGTT, compound 5c showed dose-dependent -improvement of glucose tolerance with a maximum at 30 mg/kg. It also showed reduction in area under the curve from 0 to 120 min, similar to alogliptin (standard). In Wistar rats, compound 5c causes reduction in the blood glucose level, total cholesterol, triglyceride, low density lipoprotein (LDL) and very LDL level as compared to the diabetic control group, whereas the level of high-density lipoprotein was found to be increased. Compound 5c causes improvement in antioxidant defense mechanism, as confirmed via improving superoxide dismutase, catalase, glutathione peroxidase and reducing the malondialdehyde level as compared to normal control group rats.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Triazinas/farmacologia , Animais , Antioxidantes/metabolismo , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Descoberta de Drogas/métodos , Teste de Tolerância a Glucose , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos ICR , Piperidinas/farmacologia , Ratos , Ratos Wistar , Triazinas/administração & dosagem , Triazinas/química , Uracila/análogos & derivados , Uracila/farmacologia
9.
Cancer Sci ; 110(4): 1340-1351, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30724423

RESUMO

Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open-label, multicenter, dose-escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). The primary objective was to determine the maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics and preliminary antitumor activity. Dose escalation was guided by a Bayesian Logistic Regression Model dependent on dose-limiting toxicities (DLT) in cycle 1. Of 44 adult Japanese patients with confirmed advanced solid tumors enrolled, 29 received capmatinib capsules (doses ranging from 100 mg once daily [q.d.] to 600 mg twice daily [b.i.d.]) and 15 received tablets (200 mg b.i.d. and 400 mg b.i.d.). DLT occurred in two patients: grade 2 suicidal ideation (600 mg b.i.d. capsule) and grade 3 depression (400 mg b.i.d. tablet). MTD was not reached. The highest studied dose determined to be safe as tablet was 400 mg b.i.d., whereas it is not yet determined for capsules. Most common adverse events suspected to be drug-related were increased blood creatinine, nausea, decreased appetite, vomiting and diarrhea. Following repeated daily dosing up to day 15 by q.d. or b.i.d. regimen using capsules, median time to reach maximum plasma drug concentration (Tmax ) was 1.0-4.0 hours; absorption was more rapid after dosing using tablets, with median Tmax of 1.0 hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib.


Assuntos
Antineoplásicos/administração & dosagem , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Triazinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Biomarcadores , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/metabolismo , Neoplasias/mortalidade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Análise de Sobrevida , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/farmacocinética
10.
Phytomedicine ; 53: 243-251, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30668404

RESUMO

BACKGROUND: Astragalosidic acid (LS-102) is a new water-soluble derivative of astragaloside IV - a major effective component isolated from the Chinese herb Astragali Radix. Our previous study showed that LS-102 exhibited potent cardiovascular activity. PURPOSE: The objective of this study was to investigate the pharmacokinetic properties of LS-102 after single-dose, oral administration in beagle dogs by developing and validating an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. METHOD AND RESULT: The chromatographic separation was performed on a Acquity HSS C18 column (100 mm × 2.1 mm, 1.8 µm) by a gradient elution using a mobile phase consisting of water and acetonitrile at a flow rate of 0.35 ml/min. The analytes were detected with a triple quadrupole tandem mass spectrometry in multiple reaction monitoring mode. Method validation revealed a wide linearity over the range of 2.0-10,000 ng/ml together with satisfactory intra- and inter-day precision, accuracy, and recovery. Stability testing showed that LS-102 spiked into dog plasma was stable for 4 h at room temperature, for up to 2 weeks at -80 °C, and during three freeze-thaw cycles. The method was effectively and successfully applied to the pharmacokinetics of LS-102 after oral administration (5, 10 and 20 mg/kg) to beagle dogs. Peak plasma concentrations are attained within approximately 2 h after oral administration with a half-life ranging from 1.55 h to 4.49 h. The plasma concentration-time curve of LS-102 after oral administration presents the phenomenon of a double-peak absorption phase. The peak concentration and area under the concentration-time curve of LS-102 seemed to increase with the increasing doses proportionally, that suggesting linear pharmacokinetics in dogs. Meanwhile, the doxorubicin (Dox)-injured H9c2 cell model was prepared by incubating the cells in 1 µM Dox for 24 h. MTT assay and LDH release measurement showed that LS-102 protected against Dox-induced cardiomyocyte death. CONCLUSION: The obtained results may help to guide the further pre-clinical research of LS-102 as a potentially novel cardioprotective agent.


Assuntos
Benzoxazóis/sangue , Benzoxazóis/farmacocinética , Cromatografia Líquida/métodos , Saponinas/química , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue , Triazinas/farmacocinética , Triterpenos/química , Administração Oral , Animais , Benzoxazóis/administração & dosagem , Linhagem Celular , Cromatografia Líquida de Alta Pressão/métodos , Cães , Doxorrubicina/efeitos adversos , Estabilidade de Medicamentos , Medicamentos de Ervas Chinesas/química , Feminino , Meia-Vida , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Reprodutibilidade dos Testes , Triazinas/administração & dosagem
11.
Clin Colorectal Cancer ; 18(1): e140-e149, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595557

RESUMO

BACKGROUND: The safety and efficacy of targeted therapy in older patients (≥ 70 years) with metastatic colorectal cancer is not well evaluated. PATIENTS AND METHODS: Outcomes of older patients (including overall survival [OS], progression-free survival [PFS], toxicity, and quality of life [QoL]) were compared to young patients using data from 2 large previously reported clinical trials, CO.17 (cetuximab vs. best supportive care) and CO.20 (cetuximab plus placebo vs. cetuximab plus brivanib). Only patients with wild-type KRAS tumors were included. RESULTS: A total of 251 (26.3%) of 955 patients were ≥ 70 years old. No significant differences in OS, PFS, or grade 3/4 adverse events were observed between older and younger patients treated with cetuximab (or cetuximab with placebo) in either trial. Younger patients trended toward superior OS in both CO.17 (hazard ratio = 1.80; P = .16) and CO.20 (hazard ratio = 1.34; P = .07). QoL maintenance favored younger patients in CO.17 (3.6 vs. 5.7 months; P = .046) but no difference of QoL maintenance was observed in the larger CO.20 trial (1.7 vs. 1.8 months; P = .64). Combination therapy of cetuximab and brivanib was significantly more toxic in older adults (87% vs. 77%; P = .03). CONCLUSION: OS, PFS, and toxicities were similar between older and younger patients with wild-type KRAS metastatic colorectal cancer when treated with cetuximab. Both age groups likely experience similar QoL maintenance with cetuximab. Dual targeted therapy was significantly more toxic in older patients.


Assuntos
Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Terapia de Alvo Molecular , Qualidade de Vida , Fatores Etários , Idoso , Alanina/administração & dosagem , Alanina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Metástase Neoplásica , Proteínas Proto-Oncogênicas p21(ras)/genética , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Taxa de Sobrevida , Triazinas/administração & dosagem
12.
Skin Pharmacol Physiol ; 32(1): 22-31, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30380536

RESUMO

BACKGROUND/AIMS: The data available on the skin permeability of ethylhexyl triazone (EHT), a widely used high-molecular-weight (823.1-Da) UV filter, are scarce and obtained only via in vitro studies. Therefore, we evaluated in vivo the penetration of EHT in human stratum corneum by the tape stripping technique. Moreover, the effect of EHT encapsulation in lipid microparticles (LMs) on its diffusion through the stratum corneum was examined. METHODS: LMs loaded with EHT were prepared using glyceryl behenate and phosphatidylcholine. Creams containing EHT free or encapsulated in LMs in conjunction with the two most commonly used UV filters, octyl methoxycinnamate (OMC) and butyl methoxydibenzoylmethane (BMDBM), were applied to human volunteers and the fraction of the applied sunscreen dose having penetrated into different stratum corneum layers was measured. RESULTS AND CONCLUSION: For the cream with the nonencapsulated sunscreen agent, the percentage of the applied EHT dose diffused into the stratum corneum was 21.9 ± 4.9%, not significantly different from that of the smaller-molecular-weight OMC (22.2 ± 7.6%) and BMDBM (20.5 ± 3.7%). A marked (45.7%) and statistically significant reduction in the in vivo skin penetration of EHT was attained with the cream containing microencapsulated EHT. The decreased percutaneous penetration provided by the LMs should favor the efficacy of EHT and limit potential toxicological risks.


Assuntos
Benzoatos/metabolismo , Composição de Medicamentos/métodos , Microesferas , Fosfatidilcolinas/metabolismo , Absorção Cutânea/fisiologia , Protetores Solares/metabolismo , Triazinas/metabolismo , Adulto , Benzoatos/administração & dosagem , Benzoatos/química , Feminino , Humanos , Tamanho da Partícula , Fosfatidilcolinas/administração & dosagem , Fosfatidilcolinas/química , Absorção Cutânea/efeitos dos fármacos , Protetores Solares/administração & dosagem , Triazinas/administração & dosagem , Triazinas/química , Adulto Jovem
14.
Microbiome ; 6(1): 224, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30545405

RESUMO

BACKGROUND: Antibiotics are commonly used worldwide, and pesticide is a kind of xenobiotic to which humans are frequently exposed. The interactive impact of antibiotics on pesticides has rarely been studied. We aim to investigate the effects of antibiotics on the pesticide exposure risk and whether gut microbiota altered by antibiotics has an influence on pesticide bioavailability. Furthermore, we explored the mechanisms of gut microbiota affecting the fate of pesticides in the host. RESULTS: The oral bioavailability of triazine herbicides significantly increased in the rats treated with ampicillin or antibiotic cocktails. The antibiotic-altered gut microbiota directly influenced the increased pesticide bioavailability through downregulating hepatic metabolic enzyme gene expression and upregulating intestinal absorption-related proteins. CONCLUSIONS: Antibiotics could increase the pesticide bioavailability and thereby may increase the pesticide exposure risk. The antibiotic-altered gut microbiota that could alter the hepatic metabolic enzyme gene expression and intestinal absorption-related proteome was a critical cause of the increased bioavailability. This study revealed an undiscovered potential health impact of antibiotics and reminded people to consider the co-exposed xenobiotics when taking antibiotics.


Assuntos
Antibacterianos/efeitos adversos , Bactérias/classificação , Microbioma Gastrointestinal/efeitos dos fármacos , Herbicidas/farmacocinética , Fígado/enzimologia , Triazinas/farmacocinética , Administração Oral , Animais , Antibacterianos/administração & dosagem , Bactérias/efeitos dos fármacos , Bactérias/genética , Disponibilidade Biológica , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Herbicidas/administração & dosagem , Absorção Intestinal , Fígado/efeitos dos fármacos , Masculino , Filogenia , Ratos , Ratos Sprague-Dawley , Triazinas/administração & dosagem
15.
Vet J ; 242: 74-76, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30503548

RESUMO

The purpose of this study was to determine if a low dose of diclazuril (0.5mg/kg of 1.56% diclazuril pellets) given to six healthy adult horses every 3-4 days for a total of five administrations would achieve steady-state plasma concentrations known to be inhibitory to Sarcocystis neurona and Neospora caninum. Blood was collected via venipuncture immediately before (trough concentrations) and 10h after (peak concentrations) each diclazuril administration and analysed by high-pressure liquid chromatography. The mean population-derived peak concentration was 0.284µg/mL and the mean terminal half-life was 1.6 days, but with a large variation. Thus, low dose diclazuril pellets produce steady-state plasma drug concentrations known to inhibit S. neurona (0.001µg/mL) and N. caninum (0.1µg/mL).


Assuntos
Coccidiostáticos/farmacocinética , Cavalos/metabolismo , Nitrilos/farmacocinética , Triazinas/farmacocinética , Administração Oral , Animais , Coccidiostáticos/administração & dosagem , Coccidiostáticos/sangue , Esquema de Medicação , Feminino , Cavalos/sangue , Masculino , Nitrilos/administração & dosagem , Nitrilos/sangue , Triazinas/administração & dosagem , Triazinas/sangue
16.
Parasit Vectors ; 11(1): 671, 2018 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-30587225

RESUMO

BACKGROUND: The American Heartworm Society currently recommends the use of a monthly macrocyclic lactone, a 28-day course of 10 mg/kg doxycycline BID, and the 3-dose protocol of melarsomine dihydrochloride for the treatment of canine heartworm disease. Doxycycline is necessary for the reduction of the bacterium Wolbachia, found in all heartworm life-stages. Previous price increases and decreasing availability prompted us to evaluate alternative tetracycline antibiotics, i.e. minocycline, for the reduction of Wolbachia during canine heartworm treatment. METHODS: Thirty-two heartworm-positive dogs were randomized to receive 10 mg/kg or 5 mg/kg of either doxycycline or minocycline for 28 days BID, for a total of 8 dogs per experimental group. All dogs received 6 months of Heartgard Plus® (ivermectin/pyrantel) and the 3-dose protocol of 2.5 mg/kg melarsomine dihydrochloride. Blood samples were collected prior to the initiation of treatment, every 7 days throughout tetracycline treatment, and then monthly thereafter until the dog tested negative for the presence of heartworm antigen. DNA was isolated from circulating microfilarial samples and qPCR was performed on each sample. RESULTS: A greater number of dogs in the 10 mg/kg doxycycline and minocycline treated groups experienced gastrointestinal side effects as compared to the 5 mg/kg doxycycline and minocycline treated groups. All eight dogs in the 10 mg/kg doxycycline-treated group tested negative for the presence of Wolbachia DNA by 28 days post-tetracycline treatment. A total of two dogs in both the 5 mg/kg doxycycline- and 10 mg/kg minocycline-treated groups and three dogs in the 5 mg/kg minocycline-treated group remained positive for the presence of Wolbachia DNA by the end of tetracycline treatment. CONCLUSIONS: No lung pathology was assessed in this clinical trial, therefore the clinical effect of the remaining Wolbachia DNA in the 10 mg/kg minocycline-, 5 mg/kg doxycycline- and 5 mg/kg minocycline-treated groups cannot be determined. Owner compliance in the proper administration of these tetracyclines may be impacted by the increased severe gastrointestinal side effects reported for the 10 mg/kg doxycycline- and minocycline-treated groups. We recommend that veterinarians prescribe the recommended 10 mg/kg doxycycline for canine heartworm treatment and reduce the dosage to 5 mg/kg in cases of severe gastrointestinal side effects in order to improve owner compliance in administration of medications.


Assuntos
Antibacterianos/administração & dosagem , Arsenicais/administração & dosagem , Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Doxiciclina/administração & dosagem , Filaricidas/administração & dosagem , Minociclina/administração & dosagem , Triazinas/administração & dosagem , Wolbachia/efeitos dos fármacos , Animais , Dirofilaria immitis/microbiologia , Dirofilaria immitis/fisiologia , Dirofilariose/parasitologia , Doenças do Cão/parasitologia , Cães , Doxiciclina/efeitos adversos , Quimioterapia Combinada , Feminino , Masculino , Minociclina/efeitos adversos , Wolbachia/genética , Wolbachia/fisiologia
17.
Pharmacol Res Perspect ; 6(6): e00436, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30386625

RESUMO

The aim of this study was to assess and compare the pharmacokinetics (PK) and safety of Enasidenib in healthy adult male Japanese subjects to healthy adult male Caucasian subjects. This was a phase 1, single dose study to evaluate the PK and safety of Enasidenib in healthy adult male Japanese subjects relative to healthy adult male Caucasian subjects. A total of 62 subjects (31 Japanese and 31 Caucasian) were enrolled into three dose cohorts (single doses of 50 mg, 100 mg, or 300 mg Enasidenib). Blood samples for PK assessment were collected up to 672 hours postdose. Safety was evaluated throughout the study. In the present study, we found that PK exposures of Enasidenib and its metabolite AGI-16903 for Caucasian and Japanese subjects were comparable at the 50, 100, and 300 mg dose levels, demonstrated by that the 90% confidence intervals (CIs) of geometric mean ratios for AUCs and C max between these two populations generally contained 100% from all three treatment cohorts. In conclusion, PK exposures of Enasidenib and its metabolite AGI-16903 for Caucasians and Japanese subjects were comparable and Enasidenib was safe and well tolerated with no apparent differences between Japanese and Caucasian subjects when administered as single oral doses of 50 mg, 100 mg, and 300 mg.


Assuntos
Aminopiridinas/farmacocinética , Antineoplásicos/farmacocinética , Isocitrato Desidrogenase/antagonistas & inibidores , Triazinas/farmacocinética , Adulto , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Voluntários Saudáveis , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/genética , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Adulto Jovem
19.
N Engl J Med ; 379(10): 913-923, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30184455

RESUMO

BACKGROUND: Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents. METHODS: We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population. RESULTS: In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively. CONCLUSIONS: Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354 .).


Assuntos
Antivirais/administração & dosagem , Influenza Humana/tratamento farmacológico , Oseltamivir/uso terapêutico , Oxazinas/administração & dosagem , Piridinas/administração & dosagem , Tiepinas/administração & dosagem , Triazinas/administração & dosagem , Adolescente , Adulto , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Criança , Método Duplo-Cego , Endonucleases/antagonistas & inibidores , Feminino , Humanos , Influenza Humana/virologia , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Oxazinas/efeitos adversos , Piridinas/efeitos adversos , Tiepinas/efeitos adversos , Triazinas/efeitos adversos , Carga Viral , Replicação Viral/efeitos dos fármacos , Adulto Jovem
20.
Arq Neuropsiquiatr ; 76(7): 452-458, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30066796

RESUMO

OBJECTIVE: The purpose of this study was to determine the effect of lamotrigine (LTG) and levetiracetam (LEV) as mono- and polytherapy on biochemical markers of bone turnover and bone mineral density in Egyptian adult patients with epilepsy. METHODS: Forty-eight patients were divided into four groups: two received monotherapy of either LTG or LEV, and the other two groups received polytherapy comprising (valproate [VPA] + LTG or VPA + LEV). Thirty matched healthy participants were included in the study. Participants completed a nutritional and physical activity questionnaire. Biochemical markers of bone and mineral metabolism and bone mineral density of the lumbar spine were measured at baseline and at six months. RESULTS: In the LEV monotherapy group, the bone formation markers showed a significant decrease in serum alkaline phosphatase and serum osteocalcin levels while the bone resorption marker showed a significant increase in urinary deoxypyridinoline levels. After six months of treatment, bone mineral density showed a significant decrease in all treated groups, while among monotherapy groups, this significant decrease was more prevalent in the LEV monotherapy group compared with the LTG monotherapy group. Furthermore, there was significant negative correlation between urinary deoxypyridinoline levels and bone mineral density in the LEV monotherapy group. CONCLUSION: Using new generation antiepileptics, LEV monotherapies and polytherapy showed harmful effects on bone but LTG did not.


Assuntos
Anticonvulsivantes/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Piracetam/análogos & derivados , Triazinas/efeitos adversos , Ácido Valproico/efeitos adversos , Adolescente , Adulto , Aminoácidos/urina , Anticonvulsivantes/administração & dosagem , Biomarcadores/sangue , Biomarcadores/urina , Estudos de Casos e Controles , Quimioterapia Combinada , Epilepsia/tratamento farmacológico , Feminino , Humanos , Lamotrigina , Levetiracetam , Masculino , Osteocalcina/sangue , Piracetam/administração & dosagem , Piracetam/efeitos adversos , Triazinas/administração & dosagem , Ácido Valproico/administração & dosagem , Adulto Jovem
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