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1.
Eur J Med Chem ; 181: 111576, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400709

RESUMO

The enzyme nicotinamide phosphoribosyltransferase is both a key intracellular enzyme for NAD biosynthesis (iNAMPT) and an extracellular cytokine (eNAMPT). The relationship between this latter role and the catalytic activity of the enzyme is at present unknown. With the intent of discovering inhibitors specifically able to target eNAMPT, we increased the polarity of MV78 (EC50 = 5.8 nM; IC50 = 3.1 nM), a NAMPT inhibitor previously discovered by us. The replacement of a phenyl ring with a 1,2,3-triazole bearing a protonable N,N-dialkyl methanamine group gave a series of molecules which maintained the inhibition of the enzymatic activity but were unable to cross the plasma membrane and affect cell viability in vitro. Compounds 30b and 30f can therefore be considered as the first experimental/pharmacological tools for scientists that wish to understand the role of the catalytic activity of eNAMPT. Serendipitously, we also discovered a compound (25) which, notwithstanding its high polarity, was able to cross the plasma membrane being cytotoxic, a potent NAMPT inhibitor and effective in reducing growth of triple negative mammary carcinoma in mice. In our hands, 25 lacked retinal and cardiac toxicity, although we observed a lesser toxicity of NAMPT inhibitors in general compared to other reports.


Assuntos
Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Triazóis/química , Triazóis/farmacologia , Animais , Linhagem Celular Tumoral , Química Click , Citocinas/metabolismo , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Nicotinamida Fosforribosiltransferase/metabolismo , Triazóis/farmacocinética
2.
Ecotoxicol Environ Saf ; 181: 96-105, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176252

RESUMO

Tebuconazole (TEB) is a chiral triazole fungicide that is globally marketed and used as a racemic mixture to control plant pathogens. Due to its use as a racemic mixture, TEB may exhibit enantioselective toxicokinetics toward nontarget organisms, including humans. Therefore, the in vitro enantioselective metabolism of TEB by cytochrome P450 enzymes (CYP450) was studied using human liver microsomes, and the in vivo toxicokinetic parameters were predicted. A new enantioselective, reversed-phase LC-MS/MS method was developed and validated to analyze the enantiomers of TEB and its main metabolite, 1-hydroxytebuconazole (TEBOH). In vitro metabolic parameters were obtained, and in vitro-in vivo extrapolations were performed. Michaelis-Menten and atypical biphasic kinetic profiles were observed with a total intrinsic clearance ranging from 53 to 19 mL min-1 mg-1. The in vitro-in vivo extrapolation results showed that TEB first passage effect by the liver seems to be negligible, with hepatic clearance and extraction ratios ranging from 0.53 to 5.0 mL min-1 kg-1 and 2.7-25%, respectively. Preferential metabolism of (+)-TEB to rac-TEB and (-)-TEB was observed, with preferential production of (+)-TEBOH. Furthermore, reaction phenotyping studies revealed that, despite the low hepatic clearance in the first pass metabolism of TEB, multiple human CYP450 isoforms were involved in TEB metabolism when TEBOH enantiomers were generated, mainly CYP3A4 and CYP2C9, which makes TEB accumulation in the human body more difficult due to multiple metabolic pathways.


Assuntos
Fungicidas Industriais/metabolismo , Microssomos Hepáticos/metabolismo , Triazóis/metabolismo , Cromatografia Líquida , Sistema Enzimático do Citocromo P-450/metabolismo , Fungicidas Industriais/química , Fungicidas Industriais/farmacocinética , Fungicidas Industriais/toxicidade , Humanos , Fígado/metabolismo , Estereoisomerismo , Espectrometria de Massas em Tandem , Toxicocinética , Triazóis/química , Triazóis/farmacocinética , Triazóis/toxicidade
3.
Food Chem Toxicol ; 128: 202-211, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30991128

RESUMO

Myclobutanil is a chiral triazole fungicide that is employed worldwide. Although enantiomers have the same physical-chemical properties, they may differ in terms of activity, metabolism, and toxicity. This investigation consisted of in vitro enantioselective metabolism studies that employed a human model to assess the risks of myclobutanil in humans. A LC-MS/MS enantioselective method was developed and validated. The enzymatic kinetic parameters (VMAX, KMapp, and CLINT) determined for in vitro rac-myclobutanil and S-(+)-myclobutanil metabolism revealed enantioselective differences. Furthermore, human CYP450 enzymes did not metabolize R-(-)-myclobutanil. The predicted in vivo toxicokinetic parameters indicated that S-(+)-myclobutanil may be preferentially eliminated by the liver and suffer the first-pass metabolism effect. However, because CYP450 did not metabolize R-(-)-myclobutanil, this enantiomer could reach the systemic circulation and stay longer in the human body, potentially causing toxic effects. The CYP450 isoforms CYP2C19 and CYP3A4 were involved in rac-myclobutanil and S-(+)-myclobutanil metabolism. Although there were differences in the metabolism of the myclobutanil enantiomers, in vitro inhibition studies did not show significant enantioselective differences. Overall, the present investigation suggested that myclobutanil moderately inhibits CYP2D6 and CYP2C9 in vitro and strongly inhibits CYP3A and CYP2C19 in vitro. These results provide useful scientific information for myclobutanil risk assessment in humans.


Assuntos
Inibidores das Enzimas do Citocromo P-450/toxicidade , Sistema Enzimático do Citocromo P-450/metabolismo , Fungicidas Industriais/toxicidade , Nitrilos/toxicidade , Triazóis/toxicidade , Cromatografia Líquida , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Fungicidas Industriais/farmacocinética , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Nitrilos/química , Nitrilos/farmacocinética , Reprodutibilidade dos Testes , Estereoisomerismo , Espectrometria de Massas em Tandem , Toxicocinética , Triazóis/química , Triazóis/farmacocinética
4.
Mycoses ; 62(6): 526-533, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30864238

RESUMO

BACKGROUND: Posaconazole (PCZ) is used mainly for the prevention of invasive fungal infection (IFI). METHODS: A multicentre retrospective, investigational study using a non-randomized, single-arm design carried out in six tertiary hospitals in Spain to evaluate the use of PCZ in different forms of administration in the (non-prophylactic) treatment of IFI. RESULTS: Over an eight-year-period, 67 patients were included in this study. PCZ was administered as salvage therapy (intolerant or refractory to a previous antifungal agent) in 65/67 (97%); of these, it was used against Aspergillosis (68.6%), Zygomycosis (13.4%), other moulds (8.9%) and yeast (10.5%). The median duration of PCZ therapy was 75 days. The oral solution was associated with low serum levels (<0.7 mg/L) in 63% of available patients. Clinical response at 3 and 12 months of PCZ therapy were for aspergillosis: 47.8% and 41.3%; for zygomycosis: 55.5% and 55.5%; and for other mycoses: 69.2% and 69.2%, respectively. Suspension by toxicity was only observed in 6% and 7.5% of patients at 3 and 12 months, respectively, mainly with grade III/IV elevations of liver function test (LFTs). CONCLUSIONS: Posaconazole salvage therapy, especially oral tablets, can be an effective alternative option for patients with IFI who cannot tolerate or do not respond to other antifungal therapies.


Assuntos
Antifúngicos/administração & dosagem , Micoses/tratamento farmacológico , Terapia de Salvação/métodos , Triazóis/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Análise Química do Sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espanha , Centros de Atenção Terciária , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/farmacocinética , Suspensão de Tratamento/estatística & dados numéricos
5.
PLoS One ; 14(3): e0212837, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913226

RESUMO

BACKGROUND: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS: This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7-28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. RESULTS: The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects' underlying diseases. CONCLUSION: The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01716234.


Assuntos
Antifúngicos/farmacocinética , Área Sob a Curva , Hospedeiro Imunocomprometido , Triazóis/farmacocinética , Administração Oral , Adolescente , Fatores Etários , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antineoplásicos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Lactente , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/prevenção & controle , Masculino , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Neutropenia/complicações , Neutropenia/imunologia , Estudos Prospectivos , Triazóis/administração & dosagem , Triazóis/efeitos adversos
6.
J Pharm Biomed Anal ; 168: 64-74, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30797103

RESUMO

In this study, a simple and sensitive quantitation method based on liquid chromatography combined with diode array detector and Q-Exactive-Orbitrap tandem mass spectrometry was developed for the determination of MK-8353 in rat plasma. The chromatographic separation was carried out on a Waters ACQUITY BEH C18 column by using water containing 1 mM ammonium acetate and acetonitrile containing 0.1% formic acid as mobile phase. The developed assay was linear (r > 0.999) over the concentration range of 1-1000 ng/mL. The selectivity, precision, accuracy, recovery, matrix effects and stability were all within the required limits. The validated assay has been further applied to the pharmacokinetic study of MK-8353 in rat after intravenous and oral administration, which revealed that MK-8353 showed low clearance and satisfactory bioavailability. More importantly, the metabolites of MK-8353 present in rat plasma, RLM, DLM and HLM were identified and profiled. Under the current conditions, a total of 10 metabolites were detected and their chemical structures were proposed in terms of the accurate masses and their fragment ions. Our results revealed that MK-8353 was metabolized mainly through dealkylation, demethylation, depropylation, oxygenation, sulfur oxidation and formation of lactam. Compared with animal species, no human-specific metabolite was found in HLM. This study provides overall in vitro and in vivo profiles of MK-8353, which is of great help in understanding its PK/PD profiles and in predicting human pharmacokinetic profiles.


Assuntos
Cromatografia Líquida/métodos , Indazóis/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/farmacocinética , Pirrolidinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Triazóis/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Cães , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/sangue , Masculino , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Piridinas/administração & dosagem , Piridinas/sangue , Pirrolidinas/administração & dosagem , Pirrolidinas/sangue , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Especificidade da Espécie , Triazóis/administração & dosagem , Triazóis/sangue
7.
J Pept Sci ; 25(4): e3155, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30809901

RESUMO

Previously, we reported the discovery of macrocyclic peptide triazoles (cPTs) that bind to HIV-1 Env gp120, inhibit virus cell infection with nanomolar potencies, and cause irreversible virion inactivation. Given the appealing virus-killing activity of cPTs and resistance to protease cleavage observed in vitro, we here investigated in vivo pharmacokinetics of the cPT AAR029b. AAR029b was investigated both alone and encapsulated in a PEGylated liposome formulation that was designed to slowly release inhibitor. Pharmacokinetic analysis in rats showed that the half-life of FITC-AAR029b was substantial both alone and liposome-encapsulated, 2.92 and 8.87 hours, respectively. Importantly, liposome-encapsulated FITC-AAR029b exhibited a 15-fold reduced clearance rate from serum compared with the free FITC-cPT. This work thus demonstrated both the in vivo stability of cPT alone and the extent of pharmacokinetic enhancement via liposome encapsulation. The results obtained open the way to further develop cPTs as long-acting HIV-1 inactivators against HIV-1 infection.


Assuntos
Fármacos Anti-HIV/farmacocinética , HIV-1/efeitos dos fármacos , Compostos Macrocíclicos/farmacocinética , Peptídeos/farmacocinética , Triazóis/farmacocinética , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Lipossomos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Testes de Sensibilidade Microbiana , Peptídeos/química , Peptídeos/farmacologia , Triazóis/química , Triazóis/farmacologia
8.
Nihon Yakurigaku Zasshi ; 153(2): 79-87, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30745518

RESUMO

Ravuconazole is a fourth generation azole exerting strong antifungal activity, with low drug-drug interaction and hepatic dysfunction risks. Fosravuconazole l-lysine ethanolate (fosravuconazole; NAILIN® Capsules 100 mg) was developed as a ravuconazole prodrug. Ravuconazole exerts strong antifungal activity against various pathogenic fungi including dermatophytes and Candida. Through prodrug formation, pharmacokinetic improvement was achieved, and bioavailability after oral administration reached 100%. The plasma ravuconazole concentration became 10-35 times higher than with current oral anti-onychomycosis drugs, and showed good skin and nail tissue transition plus tissue retention. This improvement obtained with fosravuconazole reflects its superior pharmacokinetic properties. We conducted a clinical trial with fosravuconazole orally administered once a day (100 mg ravuconazole) for 12 weeks in Japanese onychomycosis patients. The ravuconazole concentration in nail tissues exceeded the MIC90 against dermatophytes, even after treatment completion. Furthermore, the placebo-controlled, double-blind, comparative trial showed significantly superior effects (at 48 weeks after starting treatment, with a complete cure rate of 59.4%, a marked clinical improvement rate of 83.1%, and a mycological cure rate by direct microscopy of 82.0%). The major adverse reactions were laboratory abnormalities and gastrointestinal disorders with no severe symptoms, suggesting good tolerability. Fosravuconazole has fewer drug-drug interactions, is not affected by food, and is also expected to improve medication adherence since the administration period is only 12 weeks and there is no drug-free period as required with pulse therapy. Thus, fosravuconazole has many favorable pharmacological properties and can reasonably be expected to become a new oral treatment option for onychomycosis.


Assuntos
Antifúngicos/uso terapêutico , Lisina/uso terapêutico , Onicomicose/tratamento farmacológico , Triazóis/uso terapêutico , Administração Oral , Antifúngicos/farmacocinética , Cápsulas , Método Duplo-Cego , Humanos , Lisina/análogos & derivados , Lisina/farmacologia , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Tiazóis/farmacocinética , Tiazóis/uso terapêutico , Triazóis/farmacocinética
9.
Clin Drug Investig ; 39(5): 441-451, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30810914

RESUMO

BACKGROUND AND OBJECTIVES: Suvorexant is an orexin receptor antagonist indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. As suvorexant is metabolized primarily by Cytochrome P450 3A (CYP3A), and its pharmacokinetics may be affected by CYP3A modulators, the effects of CYP3A inhibitors (ketoconazole or diltiazem) or an inducer (rifampin [rifampicin]) on the pharmacokinetics, safety, and tolerability of suvorexant were investigated. METHODS: In two Phase I, open-label, fixed-sequence trials (Studies P008 and P038), healthy subjects received a single oral dose of suvorexant followed by co-administration with multiple once-daily doses of strong/moderate CYP3A inhibitors (ketoconazole/diltiazem) or a strong CYP3A inducer (rifampin). Treatments were administered in the morning: suvorexant 4 mg with ketoconazole 400 mg (Study P008; N = 10), suvorexant 20 mg with diltiazem 240 mg (Study P038; N = 20), and suvorexant 40 mg with rifampin 600 mg (Study P038; N = 10). Area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), maximum plasma concentration (Cmax), half-life (t½), and time to Cmax (tmax) were derived from plasma concentrations of suvorexant collected at prespecified time points up to 10 days following CYP3A inhibitor/inducer co-administration. Adverse events (AEs) were recorded. RESULTS: Co-administration with ketoconazole resulted in increased exposure to suvorexant [AUC0-∞: geometric mean ratio (GMR); 90% confidence interval (CI) 2.79 (2.35, 3.31)] while co-administration with diltiazem resulted in a lesser effect [GMR (90% CI): 2.05 (1.82, 2.30)]. Co-administration with rifampin led to a marked decrease (88%) in suvorexant exposure. Consistent with morning administration and known suvorexant pharmacology, somnolence was the most frequently reported AE. CONCLUSIONS: These results are consistent with expectations that strong CYP3A inhibitors and inducers exert marked effects on suvorexant pharmacokinetics. In the context of a limited sample size, single suvorexant doses were generally well tolerated in healthy subjects when co-administered with/without a CYP3A inhibitor/inducer.


Assuntos
Azepinas/farmacocinética , Indutores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Interações de Medicamentos/fisiologia , Antagonistas dos Receptores de Orexina/farmacocinética , Triazóis/farmacocinética , Administração Oral , Adulto , Diltiazem/farmacocinética , Voluntários Saudáveis , Humanos , Cetoconazol/farmacocinética , Masculino , Pessoa de Meia-Idade , Rifampina/administração & dosagem , Adulto Jovem
10.
Environ Sci Pollut Res Int ; 26(6): 6077-6086, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30613891

RESUMO

The present study describes the uptake and distribution of fungicides, fluopyram, and tebuconazole in tomato and bell pepper plant tissues from the soil drench application of their combination product fluopyram17.7% + tebuconazole 17.7%. For extraction and cleanup of fluopyram, its metabolite fluopyram benzamide, and tebuconazole samples, the QuEChERS method was used in conjunction with LC-MS/MS. The limit of detection (LOD) and limit of quantification (LOQ) of the method determined were 1.5 µg kg-1 and 0.005 mg kg-1, respectively, and recoveries of all analytes from sample matrices remained within the acceptable range of 70-120%. Rapid uptake of the fungicides by tomato and bell pepper plants was observed from the first day onwards. In the tomato plant, the major part of the fungicides accumulated in the roots, whereas in bell pepper plant, it accumulated both in the roots and in the leaves. Accumulation of fluopyram and tebuconazole residues was lowest in tomato and bell pepper fruits which were much below their respective maximum residue limits (MRLs). The highest residue concentration of fluopyram and tebuconazole in tomato fruits was 0.060 and 0.009 mg kg-1; the corresponding values in bell pepper fruits were 0.080 and 0.013 mg kg-1. In field soil, fluopyram residues were 3.18-3.570 mg kg-1 initially which dissipated at the half-life of 36 days. Tebuconazole concentration was 1.57-1.892 mg kg-1 initially, and it dissipated at the half-life of 44.5-49.5 days. The major metabolite of fluopyram, fluopyram benzamide, was detected in plant tissues as well as in soil, and remained within 12% of the parent compound. The results of the study indicated that fluopyram and tebuconazole are less likely of entry into food chain through intake of tomato and bell pepper fruits if these crops are grown on soil contaminated with these fungicides.


Assuntos
Benzamidas/análise , Capsicum/química , Lycopersicon esculentum/química , Resíduos de Praguicidas/análise , Piridinas/análise , Poluentes do Solo/análise , Triazóis/análise , Benzamidas/farmacocinética , Cromatografia Líquida , Frutas/química , Fungicidas Industriais/análise , Fungicidas Industriais/farmacocinética , Meia-Vida , Resíduos de Praguicidas/farmacocinética , Piridinas/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Triazóis/farmacocinética
11.
AAPS PharmSciTech ; 20(1): 24, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30604153

RESUMO

Tamoxifen is an antiestrogen drug that is widely used in the adjuvant chemotherapy of estrogen receptor-α (ERα)-positive breast cancer. Chemotherapy could suppress immune function in breast cancer patients, which may cause invasive fungal infections (IFIs). Triazoles (voriconazole, fluconazole, and itraconazole) were commonly used for IFI. The physiologically based pharmacokinetic (PBPK) models were developed to investigate the influence of different triazoles on tamoxifen pharmacokinetics in this paper. To investigate the influence of different triazoles (voriconazole, fluconazole, itraconazole) on tamoxifen pharmacokinetics. Adjusted physicochemical data and pharmacokinetic parameters of voriconazole, fluconazole, itraconazole, and tamoxifen were obtained from published literatures. PBPK models were built and verified in healthy subjects using GastroPlus™. Voriconazole, itraconazole, and tamoxifen were administered orally. Fluconazole was administered intravenously. Simulated plasma concentration-time curves of the voriconazole, fluconazole, itraconazole, and tamoxifen showed good agreement with the observed profiles, respectively. The DDI simulations showed that the pharmacokinetic parameters of tamoxifen were increased by various degrees when coadministered with different triazoles. In healthy subjects, the area under the plasma concentration-time curve from 0 to t h (AUC0-t) of tamoxifen was increased by 41%, 5%, and1% when coadministrated with voriconazole, fluconazole, and itraconazole, respectively. The PBPK models adequately characterized the pharmacokinetics of tamoxifen and triazoles. Among the three triazoles, voriconazole exhibited the greatest effect on tamoxifen pharmacokinetics. In clinical practice, an effective dosage adjustment of tamoxifen may need to be considered and TDM for tamoxifen is advisable to guide dosing and optimize therapy when coadministered with voriconazole.


Assuntos
Antifúngicos/farmacocinética , Conservadores da Densidade Óssea/farmacocinética , Modelos Biológicos , Tamoxifeno/farmacocinética , Triazóis/farmacocinética , Interações de Medicamentos/fisiologia , Feminino , Fluconazol/farmacocinética , Previsões , Humanos , Itraconazol/farmacologia , Pessoa de Meia-Idade , Voriconazol/farmacocinética
12.
Ecotoxicol Environ Saf ; 171: 247-255, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30612012

RESUMO

Enantioselective toxicokinetics, accumulation, and toxicity of myclobutanil were investigated by oral exposure of myclobutanil enantiomers to lizards. After a single oral administration, the absorption half-lives ( [Formula: see text] ) and elimination half-lives (t1/2k) were in the range of 0.133-14.828 and 3.641-17.682 h, respectively. The absorption and elimination half-lives of (+)-myclobutanil showed no significant differences from those of (-)-myclobutanil in lizard blood, whereas preferential enrichment of (-)-enantiomer was observed in the liver, fat, skin, intestine, lung and kidney. In the bioaccumulation experiments, the residue of (-)-myclobutanil was detected in most tissues at 7, 14, and 28 days, while (+)-myclobutanil was found only in lizard skin, at a concentration lower than that of (-)-myclobutanil. Thus, (-)-myclobutanil was preferentially accumulated in lizards. The transcriptional responses of metabolic enzyme genes indicated that cytochrome P450 1a1 (cyp1a1), cyp2d3, cyp2d6, cyp3a4 and cyp3a7 played a crucial role in the metabolism of (+)-myclobutanil, whereas cyp1a1, cyp2d3, cyp2d6, cyp2c8, and cyp3a4 contributed to the metabolism of (-)-myclobutanil. The difference in metabolism pathways may be a reason for the enantioselectivity of myclobutanil in lizard. Myclobutanil also affected the expression of antioxidant enzyme genes, and the (+)-myclobutanil treatment might produce higher oxidative stress in lizard liver when compared with its antipode. Hepatic histopathological changes such as hepatocellular hypertrophy, nuclear pyknosis, vacuolation, and non-zonal macrovesicular lipid accumulation were observed in the liver of lizards for both (+)-myclobutanil and (-)-myclobutanil treatments. Thus, myclobutanil could affect lizard liver upon multiple exposure. The findings of this study provide specific insights into the enantioselective metabolism and toxicity of chiral triazole fungicides in lizards.


Assuntos
Fungicidas Industriais/toxicidade , Lagartos/metabolismo , Nitrilos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Triazóis/toxicidade , Administração Oral , Animais , Antioxidantes/metabolismo , Citocromos/genética , Fungicidas Industriais/farmacocinética , Rim/metabolismo , Fígado/efeitos dos fármacos , Lagartos/genética , Nitrilos/farmacocinética , Estresse Oxidativo/genética , Pele/metabolismo , Estereoisomerismo , Distribuição Tecidual , Toxicocinética , Triazóis/farmacocinética
13.
Int J Antimicrob Agents ; 53(3): 325-329, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30639628

RESUMO

During inflammation, several cytochrome P450 enzymes are downregulated. Recently it was shown that voriconazole metabolism is reduced during inflammation. Posaconazole, another triazole with broad-spectrum antifungal activity, is metabolised only to a limited extent by cytochrome P450 enzymes and to a wider extent by phase 2 enzyme systems. The aim of this study was to investigate posaconazole concentrations during inflammation. Patients aged ≥18 years receiving posaconazole prophylaxis or treatment for fungal infections were enrolled in a prospective observational study. Samples for posaconazole and C-reactive protein (CRP) concentrations were collected routinely for each patient. Longitudinal data analysis was performed to analyse the correlation between posaconazole serum trough concentrations and CRP values, corrected for potential factors that could influence the posaconazole concentration. Between August 2015 and June 2017, 64 patients were recruited to this study. Data for 55 patients (511 posaconazole samples) were included in the final analysis. The overall median posaconazole concentration was 1.8 mg/L [interquartile range (IQR) 1-2.9 mg/L, range 0.1-7.94 mg/L] and the overall median CRP concentration was 23.5 mg/L (IQR 5-75 mg/L, range 0-457 mg/L). Longitudinal data analysis showed that only the posaconazole daily dose (in mg/kg body weight) had a significant influence on posaconazole concentration after correction for other factors (P < 0.0001). Posaconazole concentrations were not influenced by CRP concentrations (P = 0.77). Posaconazole concentrations are not influenced by inflammation, reflected by CRP concentration. Therefore, more frequent therapeutic drug monitoring of posaconazole during inflammation or after an infection subsides is not necessary.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Inflamação/patologia , Plasma/química , Triazóis/administração & dosagem , Triazóis/farmacocinética , Adulto , Idoso , Proteína C-Reativa/análise , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Micoses/tratamento farmacológico , Micoses/prevenção & controle , Estudos Prospectivos , Adulto Jovem
14.
Mater Sci Eng C Mater Biol Appl ; 97: 230-244, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30678908

RESUMO

This work aimed to develop a mucoadhesive buccal film for potential co-delivery of rizatriptan benzoate (RB) and propranolol hydrochloride (PRH). Kollicoat ® IR, polyethylene oxide (PEO), hydroxypropyl methylcellulose (HPMC K4M), glycerol, stevia, and Aloe vera gel powder (AVgel powder) were used to prepare film by solvent casting method. In order to characterize and optimize formulations, Design-Expert software with central composite design (CCD) was used. The selected independent variables were concentrations of Kollicoat ® IR, PEO, glycerol, and AVgel powder. Five selected dependent variables were in vitro disintegration time, folding endurance, swelling ratio, and in vitro drugs release. Film with 50 mg PRH, 25 mg RB, 5 mg stevia, 63 mg HPMC K4M, 100 mg Kollicoat ® IR, 66.33 mg PEO, 0.22 ml glycerol, and 0.8 mg AVgel powder was selected as optimized formulation. The optimized film was characterized by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) to evaluate morphology, chemical structure, and physical properties of the film. The mechanical properties of optimized film were measured by Santam instrument. Ex vivo permeation were studied by Franz diffusion cell, while rat buccal mucosa was used as a model membrane. The optimized film with incorporation of AVgel powder as a natural permeation enhancer could transport 73.22% of PRH and 96.11% of RB over 100 min through rat buccal mucosa and showed no buccal mucosal damage after histopathological evaluation. Overall, the optimized film could be a potential candidate for the effective treatment of migraine.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Polivinil/química , Propranolol/administração & dosagem , Triazóis/administração & dosagem , Triptaminas/administração & dosagem , Adesividade , Adesivos/química , Administração Bucal , Animais , Materiais Biocompatíveis/química , Varredura Diferencial de Calorimetria , Combinação de Medicamentos , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/instrumentação , Liberação Controlada de Fármacos , Microscopia Eletrônica de Varredura , Mucosa Bucal , Propranolol/farmacocinética , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Resistência à Tração , Triazóis/farmacocinética , Triptaminas/farmacocinética
15.
Rev. iberoam. micol ; 35(4): 186-191, oct.-dic. 2018. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-179637

RESUMO

El isavuconazol es un nuevo azol, emparentado estructuralmente con el fluconazol y el voriconazol, que presenta una absorción por vía oral muy elevada, sin efecto de primer paso, y que no es interferida por la presencia de alimentos, modificaciones del pH gástrico, ni por la mucositis. Su distribución es muy elevada, probablemente también a líquido cefalorraquídeo, a pesar de que circula en plasma unido a proteínas en un porcentaje importante. Se elimina en su totalidad por el metabolismo mediante la isoenzima CYP3A4, de ahí que se recomiende evitar el uso conjunto de inductores potentes de esta isoenzima. Además, presenta capacidad de inhibir de forma moderada la CYP3A4 y de inducir de forma débil la CYP2B6 y la glucoproteína P. En cualquier caso, esta actividad inhibitoria parece inferior a la que presentan otros azoles, lo que deriva en un uso más sencillo en el manejo de las interacciones con otros fármacos, que es probablemente la ventaja más importante de este antifúngico


Isavuconazole is a new azole, structurally related to fluconazole and voriconazole, that presents a very high oral absorption with no first-pass effect which is not interfered by the presence of food, gastric pH modifications, or mucositis. Its distribution volume is very high, probably also to cerebrospinal fluid, in spite of the fact that it circulates highly bound to plasma proteins. It is extensively metabolized through the CYP3A4 isoenzyme. Due to this reason, it is recommended to avoid co-administration with strong CYP3A4 inducers. In addition, isavuconazole may inhibit CYP3A4. Moreover, it may induce CYP2B6 and P-glycoprotein. Interestingly, this inhibitory activity seems to be lower compared to other azoles. Therefore, the management of any interaction with other medicines is easier, which is probably the most important advantage of this antifungal


Assuntos
Humanos , Micoses/tratamento farmacológico , Antifúngicos/farmacocinética , Citocromo P-450 CYP3A/síntese química , Citocromo P-450 CYP2B6/síntese química , Triazóis/farmacocinética , Composição de Medicamentos/métodos , Ciclodextrinas , Interações de Medicamentos
16.
Rev. iberoam. micol ; 35(4): 192-197, oct.-dic. 2018. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-179638

RESUMO

El tratamiento de las micosis invasoras ha evolucionado en los últimos años con la aparición de nuevos antifúngicos. Recientemente se ha aprobado un nuevo azol, isavuconazol, con un amplio espectro de acción. Esta revisión analiza el papel que puede desarrollar el isavuconazol en cada una de las micosis invasoras más importantes: candidiasis, aspergilosis, mucormicosis, infección por otros hongos filamentosos e infección por hongos dimorfos


The treatment of invasive fungal infections has deeply evolved in recent years with the inclusion of new antifungals to the therapeutic treatment arsenal. A new azole, isavuconazole, has been recently approved. This review focuses on the role of isavuconazole for treating the most important invasive fungal infections: invasive candidiasis, aspergillosis, mucormicosis, infections caused by other filamentous fungi and those caused by dimorphic fungi


Assuntos
Humanos , Micoses/tratamento farmacológico , Antifúngicos/farmacocinética , Triazóis/farmacocinética , Infecções Fúngicas Invasivas/tratamento farmacológico , Mucormicose/tratamento farmacológico , Candidíase Invasiva/tratamento farmacológico , Aspergilose/tratamento farmacológico
17.
Rev. iberoam. micol ; 35(4): 210-216, oct.-dic. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-179641

RESUMO

Los pacientes críticos sin una grave inmunosupresión es una población en la que la aspergilosis invasiva (AI) es una enfermedad en alza. El tratamiento crónico con corticoides, la enfermedad pulmonar obstructiva crónica y la cirrosis hepática son factores de riesgo repetidamente identificados en las series publicadas. No obstante, debido a la inespecificidad de los síntomas y signos en el paciente crítico y a la relativa baja capacidad diagnóstica de las pruebas complementarias, el diagnóstico de la AI supone un reto para el especialista en medicina intensiva. La aplicación de algoritmos diagnósticos adaptados al paciente crítico, cuya activación dependerá del aislamiento de Aspergillus en una muestra respiratoria, es la metodología diagnóstica más eficaz en esta población. Entre los elementos diagnósticos, la determinación de galactomanano en el líquido broncoalveolar es la prueba diagnóstica que ha demostrado más utilidad. Una vez establecida la sospecha el tratamiento debe iniciarse precozmente. El voriconazol, la anfotericina B y el isavuconazol son los tratamientos más eficaces. Aunque el voriconazol y la anfotericina B son los fármacos con mayores evidencias científicas, adolecen de problemas con relación a efectos adversos y dificultades farmacocinéticas. Por ello, el isavuconazol, que ha demostrado una elevada eficacia y seguridad en otras poblaciones, supone una potencial alternativa de extremado interés para el paciente crítico


Critically ill patients without severe immunosuppression make up a population in which invasive aspergillosis (IA) has been identified as an emergent pathology. Chronic treatment with corticosteroids, chronic obstructive pulmonary disease, and liver cirrhosis are repeatedly identified risk factors. However, due to the non-specificity of the symptoms and signs in the critical patient, and the relative low diagnostic capacity of the complementary tests, the diagnosis of the IA is a challenge for the specialist in critical care medicine. The application of diagnostic algorithms adapted to critical patients, in whom activation will depend on the isolation of Aspergillus in a respiratory specimen, is the most efficient diagnostic methodology in this population. Among the diagnostic approaches, the determination of galactomannan in bronchoalveolar fluid is the most useful diagnostic test. Once the suspicion is established, treatment should be started as soon as possible. Voriconazole, amphotericin B, and isavuconazole are the most effective treatments. Although voriconazole and amphotericin B are the drugs with the most scientific evidence, they are related with adverse effects and pharmacokinetic difficulties. Therefore, isavuconazole, which has shown high efficacy and safety in other populations, is a potential alternative of great interest for critically ill patients


Assuntos
Humanos , Infecções Fúngicas Invasivas/epidemiologia , Antifúngicos/uso terapêutico , Aspergilose/epidemiologia , Estado Terminal , Triazóis/farmacocinética , Equinocandinas/farmacocinética , Antifúngicos/farmacocinética , Aspergillus/patogenicidade , Biomarcadores/análise
18.
Rev. iberoam. micol ; 35(4): 217-221, oct.-dic. 2018. tab
Artigo em Espanhol | IBECS | ID: ibc-179642

RESUMO

Las infecciones por cigomicetos, producidas tanto por hongos mucorales como entomoftorales, se caracterizan por la invasión de los vasos sanguíneos y de otros órganos o estructuras adyacentes. Los mucorales suelen producir infección orbitorrinocerebral, pulmonar, cutánea, digestiva o diseminada y su desarrollo se ve favorecido por ciertas enfermedades de base (diabetes, insuficiencia renal) o factores de riesgo (neutropenia, inmunosupresión, sobrecarga de hierro). Se asocian a una elevada mortalidad y la clave del éxito reside en el diagnóstico y el tratamiento antifúngico precoz asociado, en la mayoría de los casos, a un desbridamiento quirúrgico amplio. En la actualidad, el isavuconazol representa una alternativa en el tratamiento de la mucormicosis refractaria o intolerante a la anfotericina B liposomal, y dadas sus características farmacocinéticas y farmacodinámicas, así como su escasa toxicidad, constituye la mejor opción para el tratamiento de mantenimiento de estas infecciones fúngicas invasivas


Infections due to zygomycetes, caused by mucorales and entomophthorales, are characterized by angioinvasion and invasion of neighboring organs or structures. Mucorales most commonly cause rhinocerebral, pulmonary, cutaneous or disseminated infection and its spread is favored by several diseases (such as diabetes or chronic kidney disease) and risk factors (neutropenia, immunosuppression, iron overload). They have a high mortality rate, and the key to success in their treatment are early diagnosis, prompt administration of antifungal treatment, and extensive surgical debridement. Currently, isavuconazole constitutes an option for the treatment of those mucormycosis refractory to liposomal amphotericin B. Due to its pharmacokinetic and pharmacodynamic characteristics and its low toxicity, it is also the best choice for maintenance therapy


Assuntos
Humanos , Mucormicose/tratamento farmacológico , Mucorales/patogenicidade , Antifúngicos/farmacocinética , Triazóis/farmacocinética , Infecções Fúngicas Invasivas/epidemiologia , Mucormicose/epidemiologia , Fatores de Risco , Anfotericina B/farmacocinética
19.
Biomed Chromatogr ; 32(11): e4333, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29978912

RESUMO

Isavuconazole is a broad-spectrum triazole antifungal drug recently approved for the therapy of both invasive aspergillosis and mucormycosis. To support a widespread therapeutic drug monitoring of isavuconazole, a simple, sensitive, and precise high-performance liquid chromatography method with UV detection was developed and fully validated for the quantification of this drug in human plasma. The method involved a combined protein precipitation-solid-phase extraction and a chromatographic separation on a Waters XTerra RP18 (150 × 4.6 mm, 3.5 µm) column using an isocratic mobile phase of ammonium acetate buffer (pH 8.0, 10 mm) and acetonitrile (45:55, v/v). The UV detection was performed at 285 nm. This method was linear (correlation coefficients ≥0.998), specific (no interference with plasma components or various potentially co-administrated drugs), sensitive (lower limit of quantification of 0.025 µg/mL), reproducible (coefficients of variation were ≤7.9%) and accurate (deviations ranged from -5.0 to 8.0%) over the range of 0.025-10 µg/mL. The method fulfilled all of the US Food and Drug Administration guidelines validation criteria and performed well in an international proficiency testing program. The assay was also successfully applied to routine therapeutic drug monitoring of patients and to drug stability investigations under various conditions.


Assuntos
Antifúngicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Nitrilos/sangue , Piridinas/sangue , Espectrofotometria Ultravioleta/métodos , Triazóis/sangue , Antifúngicos/química , Antifúngicos/farmacocinética , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Modelos Lineares , Nitrilos/química , Nitrilos/farmacocinética , Piridinas/química , Piridinas/farmacocinética , Reprodutibilidade dos Testes , Triazóis/química , Triazóis/farmacocinética
20.
J Virol ; 92(17)2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29925666

RESUMO

Current approaches do not eliminate all human immunodeficiency virus type 1 (HIV-1) maternal-to-infant transmissions (MTIT); new prevention paradigms might help avert new infections. We administered maraviroc (MVC) to rhesus macaques (RMs) to block CCR5-mediated entry, followed by repeated oral exposure of a CCR5-dependent clone of simian immunodeficiency virus (SIV) mac251 (SIVmac766). MVC significantly blocked the CCR5 coreceptor in peripheral blood mononuclear cells and tissue cells. All control animals and 60% of MVC-treated infant RMs became infected by the 6th challenge, with no significant difference between the number of exposures (P = 0.15). At the time of viral exposures, MVC plasma and tissue (including tonsil) concentrations were within the range seen in humans receiving MVC as a therapeutic. Both treated and control RMs were infected with only a single transmitted/founder variant, consistent with the dose of virus typical of HIV-1 infection. The uninfected RMs expressed the lowest levels of CCR5 on the CD4+ T cells. Ramp-up viremia was significantly delayed (P = 0.05) in the MVC-treated RMs, yet peak and postpeak viral loads were similar in treated and control RMs. In conclusion, in spite of apparent effective CCR5 blockade in infant RMs, MVC had a marginal impact on acquisition and only a minimal impact on the postinfection delay of viremia following oral SIV infection. Newly developed, more effective CCR5 blockers may have a more dramatic impact on oral SIV transmission than MVC.IMPORTANCE We have previously suggested that the very low levels of simian immunodeficiency virus (SIV) maternal-to-infant transmissions (MTIT) in African nonhuman primates that are natural hosts of SIVs are due to a low availability of target cells (CCR5+ CD4+ T cells) in the oral mucosa of the infants, rather than maternal and milk factors. To confirm this new MTIT paradigm, we performed a proof-of-concept study in which we therapeutically blocked CCR5 with maraviroc (MVC) and orally exposed MVC-treated and naive infant rhesus macaques to SIV. MVC had only a marginal effect on oral SIV transmission. However, the observation that the infant RMs that remained uninfected at the completion of the study, after 6 repeated viral challenges, had the lowest CCR5 expression on the CD4+ T cells prior to the MVC treatment appears to confirm our hypothesis, also suggesting that the partial effect of MVC is due to a limited efficacy of the drug. New, more effective CCR5 inhibitors may have a better effect in preventing SIV and HIV transmission.


Assuntos
Antagonistas dos Receptores CCR5/administração & dosagem , Cicloexanos/administração & dosagem , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Triazóis/administração & dosagem , Animais , Antagonistas dos Receptores CCR5/farmacocinética , Cicloexanos/farmacocinética , Humanos , Lactente , Maraviroc , Tonsila Palatina/química , Soro/química , Resultado do Tratamento , Triazóis/farmacocinética , Carga Viral
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