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1.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206357

RESUMO

In the current work, a simple, economical, accurate, and precise HPLC method with UV detection was developed to quantify Favipiravir (FVIR) in spiked human plasma using acyclovir (ACVR) as an internal standard in the COVID-19 pandemic time. Both FVIR and ACVR were well separated and resolved on the C18 column using the mobile phase blend of methanol:acetonitrile:20 mM phosphate buffer (pH 3.1) in an isocratic mode flow rate of 1 mL/min with a proportion of 30:10:60 %, v/v/v. The detector wavelength was set at 242 nm. Maximum recovery of FVIR and ACVR from plasma was obtained with dichloromethane (DCM) as extracting solvent. The calibration curve was found to be linear in the range of 3.1-60.0 µg/mL with regression coefficient (r2) = 0.9976. However, with acceptable r2, the calibration data's heteroscedasticity was observed, which was further reduced using weighted linear regression with weighting factor 1/x. Finally, the method was validated concerning sensitivity, accuracy (Inter and Intraday's % RE and RSD were 0.28, 0.65 and 1.00, 0.12 respectively), precision, recovery (89.99%, 89.09%, and 90.81% for LQC, MQC, and HQC, respectively), stability (% RSD for 30-day were 3.04 and 1.71 for LQC and HQC, respectively at -20 °C), and carry-over US-FDA guidance for Bioanalytical Method Validation for researchers in the COVID-19 pandemic crisis. Furthermore, there was no significant difference for selectivity when evaluated at LLOQ concentration of 3 µg/mL of FVIR and relative to the blank.


Assuntos
Amidas/análise , Amidas/sangue , Antivirais/análise , Antivirais/sangue , Bioensaio/métodos , COVID-19/tratamento farmacológico , Cromatografia Líquida de Alta Pressão/métodos , Extração Líquido-Líquido/métodos , Pirazinas/análise , Pirazinas/sangue , Aciclovir/análise , Aciclovir/sangue , COVID-19/sangue , Calibragem , Estabilidade de Medicamentos , Congelamento , Humanos , Padrões de Referência , Reprodutibilidade dos Testes , Solventes/química
2.
Artigo em Inglês | MEDLINE | ID: mdl-34052564

RESUMO

Favipiravir is a broad-spectrum inhibitor of viral RNA polymerase. It is currently used as a possible treatment for coronavirus disease 2019 (COVID-19). Pre-clinical or clinical trials of favipiravir require robust, sensitive, and accurate bioanalytical methods for quantitation of favipiravir levels. Recently, several studies have been reported about developing a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measuring favipiravir levels. However, these methods were validated predominantly for plasma samples, electrospray ionization was operated only in negative or positive mode, and clinical application of these methods has not been applied for patients with COVID-19. This study aimed was to develop a validated LC-MS/MS method for the measurement of favipiravir levels in positive and negative electrospray ionization mode and to perform a pilot study in patients with COVID-19 receiving favipiravir to demonstrate the applicability of this method in biological samples. Simple protein precipitation was used for the extraction of favipiravir from the desired matrix. Favipiravir levels were quantitated using MS / MS with an electrospray ionization source in positive and negative multiple reaction monitoring (MRM) mode. The chromatographic detection was performed on a reverse-phase Phenomenex C18 column (50 mm × 4.6 mm, 5 µm, 100 Å) with gradient elution using 0.1% formic acid in water and 0.1% formic acid in methanol as mobile phase. The method was linear over the concentration ranges of 0.048-50 µg/mL (in negative ionization mode) and 0.062-50 µg/mL (in positive ionization mode) with a correlation coefficient (r2) better than 0.998. The total run time was 3.5 min. The intra-assay and inter-assay %CV values were less than 7.2% and 8.0%, respectively. A simple, rapid and robust LC-MS / MS method was developed for the measurement of favipiravir and validation studies were performed. The validated method was successfully applied for drug level measurement in COVID-19 patients receiving favipiravir.


Assuntos
Amidas/sangue , COVID-19/tratamento farmacológico , Cromatografia Líquida/métodos , Pirazinas/sangue , Espectrometria de Massas em Tandem/métodos , Amidas/administração & dosagem , Amidas/uso terapêutico , Antivirais/administração & dosagem , Antivirais/sangue , Antivirais/uso terapêutico , COVID-19/sangue , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Pirazinas/administração & dosagem , Pirazinas/uso terapêutico , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray/métodos
3.
Anal Sci ; 37(9): 1301-1304, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-33612558

RESUMO

An in-hospital rapid method for quantifying the serum level of favipiravir (FPV) in the pharmacological treatment of COVID-19 was developed by an appropriate combination of a solid-phase extraction treatment and a reversed-phase HPLC/UV detection system. The quantification method was well-validated and applied to measuring the serum FPV level in a clinical practice at a general hospital that accepts COVID-19 patients. Furthermore, an analysis of data from our preliminary interaction analysis revealed, for the first time, that FPV selectively forms complexes with ferric (Fe3+) and cupric (Cu2+) ions.


Assuntos
Amidas/sangue , Análise Química do Sangue/métodos , COVID-19/tratamento farmacológico , Hospitais , Pirazinas/sangue , Amidas/uso terapêutico , COVID-19/sangue , Cromatografia Líquida de Alta Pressão , Humanos , Pirazinas/uso terapêutico , Fatores de Tempo
4.
PLoS Negl Trop Dis ; 15(2): e0009103, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33617533

RESUMO

Severe fever with thrombocytopenia syndrome (SFTS) is a bunyavirus infection with high mortality. Favipiravir has shown effectiveness in preventing and treating SFTS virus (SFTSV) infection in animal models. A multicenter non-randomized, uncontrolled single arm trial was conducted to collect data on the safety and the effectiveness of favipiravir in treatment of SFTS patients. All participants received favipiravir orally (first-day loading dose of 1800 mg twice a day followed by 800 mg twice a day for 7-14 days in total). SFTSV RT-PCR and biochemistry tests were performed at designated time points. Outcomes were 28-day mortality, clinical improvement, viral load evolution, and adverse events (AEs). Twenty-six patients were enrolled, of whom 23 were analyzed. Four of these 23 patients died of multi-organ failure within one week (28-day mortality rate: 17.3%). Oral favipiravir was well tolerated in the surviving patients. AEs (abnormal hepatic function and insomnia) occurred in about 20% of the patients. Clinical symptoms improved in all patients who survived from a median of day 2 to day10. SFTSV RNA levels in the patients who died were significantly higher than those in the survivors (p = 0.0029). No viral genomes were detectable in the surviving patients a median of 8 days after favipiravir administration. The 28-day mortality rate in this study was lower than those of the previous studies in Japan. The high frequency of hepatic dysfunction as an AE was observed. However, it was unclear whether this was merely a side effect of favipiravir, because liver disorders are commonly seen in SFTS patients. The results of this trial support the effectiveness of favipiravir for patients with SFTS.


Assuntos
Amidas/efeitos adversos , Amidas/uso terapêutico , Pirazinas/efeitos adversos , Pirazinas/uso terapêutico , Febre Grave com Síndrome de Trombocitopenia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Amidas/administração & dosagem , Amidas/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Japão , Hepatopatias , Masculino , Pessoa de Meia-Idade , Phlebovirus/isolamento & purificação , Pirazinas/administração & dosagem , Pirazinas/sangue , RNA Viral/isolamento & purificação , Febre Grave com Síndrome de Trombocitopenia/mortalidade , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
5.
Biomed Chromatogr ; 35(7): e5098, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33606892

RESUMO

A novel, simple and rapid UPLC-MS/MS method was developed and validated for determination of favipiravir (FAV) in human plasma. Lamivudine was used as an internal standard (IS). The Xevo TQD LC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. Precipitation with acetonitrile was used in sample preparation as it gives relatively cleaner plasma samples. The prepared samples were chromatographed using an Acquity UPLC® HSS C18 (100 × 2.1 mm, 1.8 µm) column. The mobile phase was composed of ammonium formate and methanol in a gradient mode that was pumped at a flow rate of 0.35 ml/min. The developed method was validated as per the FDA guidelines and linearity was in the range of 0.25-16 µg/ml for FAV. The intra- and inter-day precision and accuracy results were within the acceptable limits. A run time of 4.5 min and a low quantification limit of FAV allowed the application of the developed method for the determination of FAV in a bioequivalence study in healthy human volunteers.


Assuntos
Amidas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Pirazinas/sangue , Espectrometria de Massas em Tandem/métodos , Adulto , Amidas/química , Amidas/farmacocinética , Feminino , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Pirazinas/química , Pirazinas/farmacocinética , Reprodutibilidade dos Testes , Equivalência Terapêutica , Adulto Jovem
6.
J Pharm Biomed Anal ; 196: 113935, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33548872

RESUMO

BACKGROUND: The present COVID-19 pandemic has prompted worldwide repurposing of drugs. The aim of the present work was to develop and validate a two-dimensional isotope-dilution liquid chromatrography tandem mass spectrometry (ID-LC-MS/MS) method for accurate quantification of remdesivir and its active metabolite GS-441524, chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin in serum; drugs that have gained attention for repurposing in the treatment of COVID-19. METHODS: Following protein precipitation, samples were separated with a two-dimensional ultra-high performance liquid chromatography (2D-UHPLC) setup, consisting of an online solid phase extraction (SPE) coupled to an analytical column. For quantification, stable isotope-labelled analogues were used as internal standards for all analytes. The method was validated on the basis of the European Medicines Agency bioanalytical method validation protocol. RESULTS: Detuning of lopinavir and ritonavir allowed simultaneous quantification of all analytes with different concentration ranges and sensitivity with a uniform injection volume of 5 µL. The method provided robust validation results with inaccuracy and imprecision values of ≤ 9.59 % and ≤ 11.1 % for all quality controls. CONCLUSION: The presented method is suitable for accurate and simultaneous quantification of remdesivir, its metabolite GS-441525, chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin in human serum. The quantitative assay may be an efficient tool for the therapeutic drug monitoring of these potential drug candidates in COVID-19 patients in order to increase treatment efficacy and safety.


Assuntos
Antivirais/sangue , Antivirais/uso terapêutico , COVID-19/sangue , COVID-19/tratamento farmacológico , Isótopos/química , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/sangue , Alanina/análogos & derivados , Alanina/sangue , Amidas/sangue , Azitromicina/sangue , Cloroquina/sangue , Cromatografia Líquida/métodos , Furanos/sangue , Humanos , Hidroxicloroquina/sangue , Lopinavir/sangue , Pandemias/prevenção & controle , Pirazinas/sangue , Pirróis/sangue , Ritonavir/sangue , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue
8.
Eur J Pharm Sci ; 157: 105631, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33115675

RESUMO

BACKGROUND: Effective antiviral drugs for COVID-19 are still lacking. This study aims to evaluate the clinical outcomes and plasma concentrations of baloxavir acid and favipiravir in COVID-19 patients. METHODS: Favipiravir and baloxavir acid were evaluated for their antiviral activity against SARS-CoV-2 in vitro before the trial initiation. We conducted an exploratory trial with 3 arms involving hospitalized adult patients with COVID-19. Patients were randomized assigned in a 1:1:1 ratio into baloxavir marboxil group, favipiravir group, and control group. The primary outcome was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement. Virus load reduction, blood drug concentration and clinical presentation were also observed. The trial was registered with Chinese Clinical Trial Registry (ChiCTR 2000029544). RESULTS: Baloxavir acid showed antiviral activity in vitro with the half-maximal effective concentration (EC50) of 5.48 µM comparable to arbidol and lopinavir, but favipiravir didn't demonstrate significant antiviral activity up to 100 µM. Thirty patients were enrolled. The percentage of patients who turned viral negative after 14-day treatment was 70%, 77%, and 100% in the baloxavir marboxil, favipiravir, and control group respectively, with the medians of time from randomization to clinical improvement was 14, 14 and 15 days, respectively. One reason for the lack of virological effect and clinical benefits may be due to insufficient concentrations of these drugs relative to their antiviral activities. One of the limitations of this study is the time from symptom onset to randomization, especially in the baloxavir marboxil and control groups, which is higher than the favipiravir group. CONCLUSIONS: Our findings could not prove a benefit of addition of either baloxavir marboxil or favipiravir under the trial dosages to the existing standard treatment.


Assuntos
Amidas , COVID-19 , Dibenzotiepinas , Morfolinas , Pirazinas , Piridonas , Triazinas , Amidas/administração & dosagem , Amidas/sangue , Amidas/farmacocinética , Antivirais/administração & dosagem , Antivirais/sangue , Antivirais/farmacocinética , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/fisiopatologia , Dibenzotiepinas/administração & dosagem , Dibenzotiepinas/sangue , Dibenzotiepinas/farmacocinética , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/sangue , Morfolinas/farmacocinética , Pirazinas/administração & dosagem , Pirazinas/sangue , Pirazinas/farmacocinética , Piridonas/administração & dosagem , Piridonas/sangue , Piridonas/farmacocinética , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Avaliação de Sintomas , Resultado do Tratamento , Triazinas/administração & dosagem , Triazinas/sangue , Triazinas/farmacocinética , Carga Viral/efeitos dos fármacos
9.
Spectrochim Acta A Mol Biomol Spectrosc ; 249: 119241, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333412

RESUMO

The present work describes development of rapid, robust, sensitive and green spectrofluorimetric method for determination of favipiravir (FAV). Different factors affecting fluorescence were carefully studied and Box Behnken Design was applied to optimize experimental parameters. The proposed method is based on measuring native fluorescence of FAV in 0.2 M borate buffer (pH 8.0) at 432 nm after excitation at 361 nm. There was a linear relationship between FAV concentration and relative fluorescence intensity over the range 40-280 ng/mL with limit of detection of 9.44 ng/mL and quantitation limit of 28.60 ng/mL. The method was successfully implemented for determination of FAV in its pharmaceutical formulation with mean % recovery of 99.26 ± 0.87. Moreover, the high sensitivity of the method allowed determination of FAV in spiked human plasma over a range of 48-192 ng/mL. The proposed spectrofluorimetric method was proved to be eco-friendly according to analytical eco-scale.


Assuntos
Amidas/sangue , Antivirais/sangue , COVID-19/sangue , COVID-19/tratamento farmacológico , Pirazinas/sangue , Espectrometria de Fluorescência/métodos , Amidas/análise , Amidas/uso terapêutico , Antivirais/análise , Antivirais/uso terapêutico , Análise Química do Sangue/métodos , Análise Química do Sangue/estatística & dados numéricos , Humanos , Limite de Detecção , Pirazinas/análise , Pirazinas/uso terapêutico , SARS-CoV-2 , Sensibilidade e Especificidade , Espectrometria de Fluorescência/estatística & dados numéricos
10.
Biomed Chromatogr ; 34(10): e4918, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32533577

RESUMO

From the point of view of drug efficacy and safety, pharmacokinetic profiles of both In this work, a sensitive and reliable liquid chromatographic-tandem mass spectrometric method was established for simultaneous determination of sutetinib and N-oxide metabolite (SNO) in human plasma and further applied to a pharmacokinetic study. Analytes were extracted from plasma samples (100 µl) via acetonitrile-induced protein precipitation and separated on a C18 column using ammonium acetate with ammonium hydroxide and acetonitrile as the mobile phase. Positive electrospray ionization was carried out through multiple reaction monitoring with transitions of m/z 440.2 → 367.1 and 446.2 → 367.1 for sutetinib and SNO, respectively. The method was linear within the concentration range of 0.5-100 ng/ml for both analytes. The precision, accuracy, selectivity, recovery and matrix effect of this method all met the requirements of bioanalytical guidance. In addition, a plasma stability assessment demonstrated unexpected results. Sutetinib was prone to form covalent conjugates with plasma albumin in vitro. The degree of covalent binding increased with increasing temperature, resulting in a significant decrease in its plasma concentrations. However, SNO could not easily bind with albumin owing to steric hindrance or electronegativity. Furthermore, sutetinib and SNO remained stable when blood and plasma samples were kept on wet ice. The validated method was successfully employed for the pharmacokinetic evaluation of sutetinib in patients with advanced malignant solid tumors.


Assuntos
Amidas/sangue , Antineoplásicos/sangue , Cromatografia Líquida/métodos , Óxidos/sangue , Inibidores de Proteínas Quinases/sangue , Amidas/farmacocinética , Amidas/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Humanos , Limite de Detecção , Modelos Lineares , Neoplasias/tratamento farmacológico , Óxidos/farmacocinética , Óxidos/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
11.
Int J Mol Sci ; 21(9)2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32403407

RESUMO

Growing evidence highlights the endocannabinoid (EC) system involvement in cancer progression. Lipid mediators of this system are secreted by hematopoietic cells, including the ECs 2-arachidonoyl-glycerol (2AG) and arachidonoyl-ethanolamide (AEA), the 2AG metabolite 1AG, and members of N-acylethanolamine (NAE) family-palmitoyl-ethanolamide (PEA) and oleoyl-ethanolamide (OEA). However, the relevance of the EC system in myeloproliferative neoplasms (MPN) was never investigated. We explored the EC plasma profile in 55 MPN patients, including myelofibrosis (MF; n = 41), polycythemia vera (PV; n = 9), and essential thrombocythemia (ET; n = 5) subclasses and in 10 healthy controls (HC). AEA, PEA, OEA, 2AG, and 1AG plasma levels were measured by LC-MS/MS. Overall considered, MPN patients displayed similar EC and NAE levels compared to HC. Nonetheless, AEA levels in MPN were directly associated with the platelet count. MF patients showed higher levels of the sum of 2AG and 1AG compared to ET and PV patients, higher OEA/AEA ratios compared to HC and ET patients, and higher OEA/PEA ratios compared to HC. Furthermore, the sum of 2AG and 1AG positively correlated with JAK2V617F variant allele frequency and splenomegaly in MF and was elevated in high-risk PV patients compared to in low-risk PV patients. In conclusion, our work revealed specific alterations of ECs and NAE plasma profile in MPN subclasses and potentially relevant associations with disease severity.


Assuntos
Endocanabinoides/sangue , Etanolaminas/sangue , Transtornos Mieloproliferativos/sangue , Policitemia Vera/sangue , Mielofibrose Primária/sangue , Trombocitemia Essencial/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Amidas/sangue , Ácidos Araquidônicos/sangue , Cromatografia Líquida/métodos , Feminino , Glicerídeos/sangue , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Ácidos Oleicos/sangue , Ácidos Palmíticos/sangue , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Alcamidas Poli-Insaturadas/sangue , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/genética , Espectrometria de Massas em Tandem/métodos , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/genética
12.
Clin Pharmacol Ther ; 108(2): 242-247, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32246834

RESUMO

An outbreak of 2019-nCoV infection has spread across the world. No specific antiviral drugs have been approved for the treatment of COVID-2019. In addition to the recommended antiviral drugs, such as interferon-ɑ, lopinavir/ritonavir, ribavirin, and chloroquine phosphate, some clinical trials focusing on virus RNA-dependent RNA polymerase (RdRp) inhibitors have been registered and initiated. Favipiravir, a purine nucleic acid analog and potent RdRp inhibitor approved for use in influenza, is also considered in several clinical trials. Herein, we summarized the pharmacokinetic characteristics of favipiravir and possible drug-drug interactions from the view of drug metabolism. We hope this will be helpful for the design of clinical trials for favipiravir in COVID-2019, as data regarding in vitro virus inhibition and efficacy in preclinical animal studies are still not available.


Assuntos
Amidas/farmacocinética , Antivirais/farmacocinética , Pirazinas/farmacocinética , Acetaminofen/farmacocinética , Amidas/administração & dosagem , Amidas/sangue , Animais , Antivirais/administração & dosagem , Antivirais/sangue , COVID-19/tratamento farmacológico , Ensaios Clínicos como Assunto , Infecções por Coronavirus/tratamento farmacológico , Interações Medicamentosas , Humanos , Pirazinas/administração & dosagem , Pirazinas/sangue
13.
Psychol Med ; 50(11): 1862-1871, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31422779

RESUMO

BACKGROUND: Evidence has been accumulating regarding alterations in components of the endocannabinoid system in patients with psychosis. Of all the putative risk factors associated with psychosis, being at clinical high-risk for psychosis (CHR) has the strongest association with the onset of psychosis, and exposure to childhood trauma has been linked to an increased risk of development of psychotic disorder. We aimed to investigate whether being at-risk for psychosis and exposure to childhood trauma were associated with altered endocannabinoid levels. METHOD: We compared 33 CHR participants with 58 healthy controls (HC) and collected information about previous exposure to childhood trauma as well as plasma samples to analyse endocannabinoid levels. RESULTS: Individuals with both CHR and experience of childhood trauma had higher N-palmitoylethanolamine (p < 0.001) and anandamide (p < 0.001) levels in peripheral blood compared to HC and those with no childhood trauma. There was also a significant correlation between N-palmitoylethanolamine levels and symptoms as well as childhood trauma. CONCLUSIONS: Our results suggest an association between CHR and/or childhood maltreatment and elevated endocannabinoid levels in peripheral blood, with a greater alteration in those with both CHR status and history of childhood maltreatment compared to those with either of those risks alone. Furthermore, endocannabinoid levels increased linearly with the number of risk factors and elevated endocannabinoid levels correlated with the severity of CHR symptoms and extent of childhood maltreatment. Further studies in larger cohorts, employing longitudinal designs are needed to confirm these findings and delineate the precise role of endocannabinoid alterations in the pathophysiology of psychosis.


Assuntos
Experiências Adversas da Infância/psicologia , Amidas/sangue , Ácidos Araquidônicos/sangue , Endocanabinoides/sangue , Etanolaminas/sangue , Ácidos Palmíticos/sangue , Alcamidas Poli-Insaturadas/sangue , Transtornos Psicóticos/sangue , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Sintomas Prodrômicos , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/etiologia , Fatores de Risco , Adulto Jovem
15.
Sci Rep ; 9(1): 1785, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30741966

RESUMO

Favipiravir (T705; 6-fluoro-3-hydroxypyrazine-2-carboxamide) is a pyrazine analog that has demonstrated potent antiviral activity against a broad spectrum of viruses in multiple in vivo disease models. To better understand the compounds anti-viral activity, assessment of the drug's biodistribution and kinetics in vivo may lend insight into how best to evaluate the compound efficacy preclinically and to contribute to the design of clinical studies to take into account the compound's pharmacokinetic distribution and kinetics. In the current study, a method for synthesis of [18F]favipiravir was developed and the biodistribution in mice naïve to and pre-dosed with favipiravir was assessed by PET and gamma counting of tissue samples. Fluorine-18 labeling of favipiravir was achieved in a one-pot, two-step synthesis using a commercially available precursor, methyl-5-chloroisoxazolo[4,5-b]pyrazine-3-carboxylate, with an overall radiochemical yield of 15-24%, a molar activity of 37-74 GBq/µmol in a 70 minute synthesis time. [18F]favipiravir tissue uptake and distribution was similar in naïve and pre-dosed mice; however, in the pre-dosed animals plasma clearance was more rapid and tissue clearance appeared to be prolonged. In conclusion, application of PET to the evaluation of favipiravir has demonstrated the importance of dosing regimen on the distribution and tissue uptake and clearance of the molecule. Favipiravir is cleared through the kidney as previously reported but the liver and intestinal excretion may also play an important role in compound elimination. Measurement of the tissue uptake of favipiravir as determined by PET may be a more important indicator of a compound's potential efficacy than purely monitoring plasma parameters such as viremia and drug levels.


Assuntos
Amidas/síntese química , Amidas/farmacocinética , Antivirais/síntese química , Antivirais/farmacocinética , Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons/métodos , Pirazinas/síntese química , Pirazinas/farmacocinética , Amidas/sangue , Animais , Antivirais/sangue , Camundongos , Camundongos Endogâmicos C3H , Pirazinas/sangue , Compostos Radiofarmacêuticos/química , Distribuição Tecidual
16.
J Pharm Biomed Anal ; 162: 130-139, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30236821

RESUMO

N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) is a novel valproic acid derivative that has shown anti-proliferative activity against epitheloid cervix carcinoma (HeLa), rhabdomyosarcoma (A204), and several breast cancer cell lines. The aim of this research was to evaluate the pharmacokinetic profile and tissue distribution of HO-AAVPA in Wistar rats, as well as its human serum albumin binding potential by experimental and in silico methods. A single dose of HO-AAVPA was given to male rats by intravenous, intragastric or intraperitoneal routes at doses of 25, 100, and 100 mg/kg, respectively. Then, blood samples were drawn at predetermined intervals of time, and the HO-AAVPA concentration in the plasma was quantified with a validated HPLC method. The elimination half-life (t1/2) was approximately 222 min, and the systemic clearance (CL) and apparent volume of distribution (Vd) were 2.20 mL/min/kg and 0.70 L/kg, respectively. The absolute oral bioavailability of HO-AAVPA was 33.8%, and the binding rate of HO-AAVPA with rat plasma proteins was between 66.2% and 83.0%. Additionally, in silico, UV and Raman spectroscopy data showed weak interactions between the test compound and human serum albumin. Thus, the results that were obtained demonstrated that despite its low oral bioavailability, the potential anticancer agent HO-AAVPA exhibits acceptable pharmacokinetic properties that would allow it to reach its site of action and exert its pharmacological effect in Wistar Rats, and it has a convenient profile for future assays to evaluate its human applications.


Assuntos
Amidas/farmacocinética , Antineoplásicos/farmacocinética , Pentanos/farmacocinética , Albumina Sérica Humana/metabolismo , Ácido Valproico/farmacocinética , Administração Oral , Amidas/administração & dosagem , Amidas/sangue , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Sítios de Ligação , Disponibilidade Biológica , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pentanos/administração & dosagem , Pentanos/sangue , Ligação Proteica , Ratos Wistar , Distribuição Tecidual , Ácido Valproico/administração & dosagem , Ácido Valproico/sangue
17.
Talanta ; 193: 29-36, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30368294

RESUMO

The recent growing interest in primary fatty acid amides (PFAMs) is due to the broad range of physiological effects they exhibit as bioindicator of pathological states. These bioactive lipids are usually in biological samples at the nanomolar level, making their detection and identification a challenging task. A method for quantitative analysis of seven main PFAMs (lauramide, myristamide, linoleamide, palmitamide, oleamide, stearamide and behenamide) in four human biofluids -namely, urine, plasma, saliva and sweat- is here reported. Two sample preparation procedures were compared to test their efficiency in each biofluid: solid-phase extraction (SPE) and protein precipitation. The latter was the best for plasma and urine, while the analysis of saliva and sweat required an SPE step for subsequent suited determination of PFAMs. Detection of the seven metabolites was performed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring (MRM) mode. Quantitative analysis was supported on the use of stable isotopically labeled internal standards (SIL-ISs) in the calibration method, which required the synthesis of each IS from the precursor deuterated fatty acids. Detection limits for the target analytes were within 0.3-3 ng mL-1. The method was applied to a small cohort of male and female volunteers (n = 6) to estimate the relative concentration profiles in the different biofluids. The analytical features of the method supported its applicability in clinical studies aimed at elucidating the role of PFAMs metabolism.


Assuntos
Amidas/sangue , Amidas/urina , Ácidos Graxos/sangue , Ácidos Graxos/urina , Amidas/síntese química , Amidas/normas , Cromatografia Líquida/métodos , Deutério , Ácidos Graxos/síntese química , Ácidos Graxos/normas , Feminino , Humanos , Limite de Detecção , Masculino , Padrões de Referência , Reprodutibilidade dos Testes , Saliva/química , Suor/química , Espectrometria de Massas em Tandem/métodos
18.
Bioorg Med Chem Lett ; 28(14): 2446-2450, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29929882

RESUMO

The dipeptide amide H-Phe-Phe-NH2 (1) that previously was identified as a ligand for the substance P 1-7 (SP1-7) binding site exerts intriguing results in animal models of neuropathic pain after central but not after peripheral administration. The dipeptide 1 is derived from stepwise modifications of the anti-nociceptive heptapeptide SP1-7 and the tetrapeptide endomorphin-2 that is also binding to the SP1-7 site. We herein report a strong anti-allodynic effect of a new H-Phe-Phe-NH2 peptidomimetic (4) comprising an imidazole ring as a bioisosteric element, in the spare nerve injury (SNI) mice model after peripheral administration. Peptidomimetic 4 was stable in plasma, displayed a fair membrane permeability and a favorable neurotoxic profile. Moreover, the effective dose (ED50) of 4 was superior as compared to gabapentin and morphine that are used in clinic.


Assuntos
Amidas/farmacologia , Dipeptídeos/farmacologia , Hiperalgesia/tratamento farmacológico , Imidazóis/farmacologia , Peptidomiméticos/farmacologia , Nervos Espinhais/efeitos dos fármacos , Nervos Espinhais/lesões , Amidas/sangue , Amidas/química , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dipeptídeos/sangue , Dipeptídeos/química , Relação Dose-Resposta a Droga , Imidazóis/sangue , Imidazóis/química , Injeções Intraperitoneais , Camundongos , Estrutura Molecular , Peptidomiméticos/sangue , Peptidomiméticos/química , Ratos
19.
J Microencapsul ; 35(4): 313-326, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29683357

RESUMO

Rhein (RH) has many bioactivities, but the application was limited of its poor solubility. The present study aimed to establish an efficient method for the synthesis of rhein amide derivatives (RAD) to increase the solubility and anti-tumour activity. RAD exhibited stronger anti-tumour activity than RH in MTT assay. The solubility and oil/water partition coefficient results indicated that rhein-phenylalanine and rhein-isoleucine have better absorption effect, which was consolidated in pharmacokinetic study. Then, rhein-phenylalanine and rhein-isoleucine were prepared into nanocrystals via the precipitation high-pressure homogenisation method. Additionally, the nanocrystals both displayed much higher dissolution profiles than the bulk drugs. Pharmacokinetics study indicated that the AUC0-∞ and Cmax of nanocrystals increased markedly (p < 0.01). However, the concentration of RH-Phe-NC was far less than RH-Ile-NC in plasma. Consequently, RH-Ile-NC was validated to be an applicable way to improve the bioavailability of RH, which owns a promising future in clinical application.


Assuntos
Antraquinonas/sangue , Antraquinonas/química , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/química , Nanopartículas/química , Amidas/sangue , Amidas/síntese química , Amidas/química , Animais , Antraquinonas/síntese química , Disponibilidade Biológica , Inibidores Enzimáticos/síntese química , Células Hep G2 , Humanos , Isoleucina/análogos & derivados , Isoleucina/sangue , Isoleucina/síntese química , Masculino , Fenilalanina/análogos & derivados , Fenilalanina/sangue , Fenilalanina/síntese química , Ratos Sprague-Dawley , Solubilidade
20.
Bioorg Chem ; 76: 370-379, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29241109

RESUMO

Naproxen (nap) is belonging to Non-steriodal anti-inflammatory drugs (NSAIDs) group of drugs that characterized by their free carboxylic group. The therapeutic activity of nap is usually accompanied by GI untoward side effects. Recently synthesized naproxen amides of some amino acid esters prodrugs to mask the free carboxylic group were reported. Those prodrugs showed a promising colorectal cancer chemopreventive activity. The current study aims to investigate the fate and hydrolysis of the prodrugs kinetically in different pH conditions, simulated gastric and intestinal fluids with pHs of 1.2, 5.5 and 7.4 in vitro at 37 °C. The effect of enzymes on the hydrolysis of prodrugs was also studied through incubation of these prodrugs at 37 °C in human plasma and rat liver homogenates. The pharmacokinetic parameters of selected prodrugs and the liberated nap were studied after oral and intraperitoneal administration in male wistar rats. The results showed the hydrolysis of naproxen amides of amino acid esters to nap through two steps first by degradation of the ester moiety to form the amide of nap with amino acid and the second was through the degradation of the amide link to liberate nap. The two reactions were followed and studied kinetically where K1 and K2 (rate constants of degradation) is reported. The hydrolysis of prodrugs was faster in liver homogenates than in plasma. The relative bioavailability of the liberated nap in vivo was higher in case of prodrug containing ethyl glycinate moiety than that occupied l-valine ethyl ester moiety. Each of nap. prodrugs containing ethyl glycinate and l-valine ethyl ester moieties appears promising in liberating nap, decreasing direct GI side effect and consequently their colorectal cancer chemopreventive activity.


Assuntos
Amidas/farmacocinética , Aminoácidos/farmacocinética , Anticarcinógenos/farmacocinética , Naproxeno/análogos & derivados , Naproxeno/farmacocinética , Pró-Fármacos/farmacocinética , Administração Oral , Amidas/administração & dosagem , Amidas/sangue , Amidas/química , Aminoácidos/administração & dosagem , Aminoácidos/sangue , Aminoácidos/química , Animais , Anticarcinógenos/administração & dosagem , Anticarcinógenos/sangue , Anticarcinógenos/química , Neoplasias Colorretais/tratamento farmacológico , Estabilidade de Medicamentos , Ésteres/administração & dosagem , Ésteres/sangue , Ésteres/química , Ésteres/farmacocinética , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Injeções Intraperitoneais , Cinética , Fígado/metabolismo , Masculino , Naproxeno/administração & dosagem , Naproxeno/sangue , Pró-Fármacos/administração & dosagem , Pró-Fármacos/análise , Pró-Fármacos/química , Ratos Wistar
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