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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.
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
5.
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
6.
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
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.
Biomed Chromatogr ; 35(4): e5028, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33179270

RESUMO

Gilteritinib, an oral inhibitor of FMS-like tyrosine kinase 3 (FLT3), is a standard treatment for FLT3-mutated acute myeloid leukemia. We developed a simple HPLC-UV-based method for determining the concentration of gilteritinib in human plasma. The analysis requires the extraction of a 200-µL plasma sample and the precipitation of proteins by solid-phase extraction. Gilteritinib was isocratically separated within 10 min using a mobile phase of acetonitrile:0.5% monopotassium phosphate (KH2 PO4 , pH 3.5, 28:72, v/v) on a Capcell Pack C18 MG II (250 × 4.6 mm) column at a flow rate of 1.0 mL/min and monitored at 250 nm. The calibration curve was found to be linear within a plasma concentration range of 25-2500 ng/mL, with the coefficient of determination (r2 ) being 0.9997. The coefficients of intra-day and inter-day validation were 2.3-3.7 and 1.3-5.2%, respectively. The accuracy and recovery of the assay were -9.6 to 0.1 and >81.8%, respectively. This HPLC-UV method for determining the plasma concentration of gilteritinib is simple and can be effectively applied to routine drug monitoring.


Assuntos
Compostos de Anilina/sangue , Cromatografia Líquida de Alta Pressão/métodos , Pirazinas/sangue , Idoso , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Modelos Lineares , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria Ultravioleta
10.
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
12.
J Pharm Biomed Anal ; 190: 113496, 2020 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-32768890

RESUMO

In the present study, an accurate, simple and fast bioanalytical method based on ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technique for simultaneous quantification of plasma selexipag and its main metabolite ACT-333679 concentrations in rats was optimized and established. The purpose of chromatographic separation of selexipag, ACT-333679 and the internal standard (IS, diazepam) was accomplished using an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 µm) column. The mobile phase was consisted of acetonitrile (solution A) and 0.1 % formic acid in water (solution B) in a linear gradient elution procedure with a flow rate of 0.40 mL/min. The measurement of the analytes and IS was explored using a XEVO TQ-S triple quadrupole tandem mass spectrometer, which was comprised with electrospray ionization (ESI) source in positive ion mode. Selected multiple reaction monitoring (MRM) mode was employed to detect the parent-to-daughter ion transitions as follows: m/z 497.4 → 302.2 for selexipag, m/z 420.1 → 378.2 for ACT-333679, and m/z 285.0 → 154.0 for diazepam (IS), respectively. The new UPLC-MS/MS method showed good linearity respectively at the calibration curve range of 0.05-50 ng/mL for selexipag, and 0.05-250 ng/mL for ACT-333679. The intra- and inter-day of accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery and matrix effect were also met the requirements. The newly developed UPLC-MS/MS assay was forward successfully used to describe the pharmacokinetic profiles of selexipag and ACT-333679 in rats after oral treatment with 6.0 mg/kg selexipag.


Assuntos
Acetamidas , Acetatos , Pirazinas , Espectrometria de Massas em Tandem , Acetamidas/sangue , Acetamidas/farmacocinética , Acetatos/sangue , Acetatos/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Pirazinas/sangue , Pirazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
13.
Drug Des Devel Ther ; 14: 2061-2067, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32546970

RESUMO

Background: Gilteritinib, a novel, potent FLT3/AXL inhibitor, was recently approved in Japan and USA for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation. Purpose and Methods: In this study, we aimed to develop and validate a sensitive and simple ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the quantification of gilteritinib in plasma and to investigate whether CYP3A4 inhibitors (fluconazole and itraconazole) could influence the pharmacokinetics of gilteritinib from a drug-drug interaction study in rats. Sample preparation was done by a simple protein crash with acetonitrile containing the internal standard (IS) pirfenidone, followed by UPLC-MS/MS quantification. Results: The assay was successfully validated in a 1-500 ng/mL calibration range for gilteritinib, where the lower limit of quantification (LLOQ) was set at 1 ng/mL. The intra-day and inter-day precisions for gilteritinib were less than 10.6%, and the accuracies were in the range of -14.5% to 11.1%. Recovery and matrix effect of the analyte and IS were acceptable, and the analyte was stable during the assay and storage in plasma samples. The validated UPLC-MS/MS method was successfully applied to a drug-drug interaction study between gilteritinib and CYP3A4 inhibitors (fluconazole and itraconazole) in rats. Itraconazole significantly increased the exposure of gilteritinib, and affected the pharmacokinetics of gilteritinib in rats, not fluconazole. Conclusion: A further clinical study should be conducted to investigate the effect of itraconazole on the metabolism of gilteritinib in subjects.


Assuntos
Compostos de Anilina/sangue , Fluconazol/sangue , Itraconazol/sangue , Pirazinas/sangue , Administração Oral , Compostos de Anilina/administração & dosagem , Compostos de Anilina/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Interações Medicamentosas , Fluconazol/administração & dosagem , Fluconazol/farmacocinética , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Masculino , Pirazinas/administração & dosagem , Pirazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
14.
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
15.
Biomed Chromatogr ; 34(9): e4869, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32346872

RESUMO

To investigate the effect of ligustrazine on the pharmacokinetic profile of tanshinol after intravenous administration in rats, a sensitive liquid chromatography tandem mass spectrometry method was developed and validated for quantitative determination of tanshinol and ligustrazine in rat plasma. After prepared by protein precipitation, the analytes were separated on a Waters Acquity HSS T3 column (100 × 2.1 mm, 1.8µm) and eluted by 0.1% formic acid in water and acetonitrile at a flow rate of 0.4 ml/min. The precursor-product ion transitions were m/z 197.0 → 135.0 for tanshinol, m/z 417.1 → 255.1 for liquiritin (internal standard) in negative ion mode and m/z 137.1 → 55.0 for ligustrazine in positive ion mode. To avoid the interference of tanshinol metabolite transformation, the stability of analytes in samples collected after administration was assessed. The validated method was successfully applied to a pharmacokinetic study after intravenous administration of single tanshinol and Danshen Chuanxiongqin Injection. After Danshen Chuanxiongqin injection administration, the values of elimination half-time, area under the concentration-time curve and Co were 0.36 ± 0.13 h, 1.29 ± 0.37 µg/ml h and 10.51 ± 2.58 µg/ml for male rats, respectively. In the single tanshinol group, the corresponding values were 0.56 ± 0.24 h, 1.85 ± 0.44 µg/ml h and 14.11 ± 2.26 µg/ml for male rats-30-40% higher than those for the Danshen Chuanxiongqin Injection group. There was a significant different between male and female rats. This study provided information on the influence of ligustrazine on the pharmacokinetic characteristics of tanshinol after intravenous administration of Danshen Chuanxiongqin Injection in rats, which will be helpful for its clinical application.


Assuntos
Ácidos Cafeicos , Pirazinas , Administração Intravenosa , Animais , Ácidos Cafeicos/administração & dosagem , Ácidos Cafeicos/sangue , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Modelos Lineares , Masculino , Pirazinas/administração & dosagem , Pirazinas/sangue , Pirazinas/química , Pirazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Salvia miltiorrhiza , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos
16.
Arch Pharm Res ; 42(12): 1092-1100, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31797253

RESUMO

Gestational diabetes mellitus (GDM) is a disease characterized by insufficient insulin secretion and glucose metabolic disorder during pregnancy. Tetramethylpyrazine has been reported to inhibit endoplasmic reticulum (ER) stress and high glucose-induced inflammation, which are closely associated with GDM. This study aimed to investigate the effects of tetramethylpyrazine on inflammatory responses, ER stress and oxidative stress of the placenta in a mouse model of GDM. Our results showed that tetramethylpyrazine treatment significantly alleviated the GDM symptoms characterized by low body weight and serum insulin levels, high blood glucose, and decreased ß-cell function in pregnant C57BL/KsJdb/+ mice. In addition, tetramethylpyrazine reduced the level of malondialdehyde, and increased the levels of superoxide dismutase, glutathione peroxidase and glutathione. Moreover, tetramethylpyrazine decreased the total serum cholesterol, serum triglyceride, and serum low-density lipoprotein levels and increased the high-density lipoprotein level. Further, tetramethylpyrazine regulated the levels of serum and placental inflammatory factors and the expression of ER stress related proteins. Taken together, the present study demonstrated that tetramethylpyrazine attenuated placental oxidative stress, inflammatory responses and ER stress in GDM mice.


Assuntos
Diabetes Gestacional/tratamento farmacológico , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Placenta/efeitos dos fármacos , Pirazinas/farmacologia , Administração Oral , Animais , Diabetes Gestacional/metabolismo , Relação Dose-Resposta a Droga , Feminino , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Placenta/metabolismo , Gravidez , Pirazinas/administração & dosagem , Pirazinas/sangue
17.
PLoS One ; 14(9): e0221994, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31527867

RESUMO

Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9-97.3%). Duration of PR was 125-401 days; median SD duration was 297 days (min-max, 50-1519 days). Median progression-free survival was 19.5 months (95% CI 10.4-28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.


Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Tumores Neuroendócrinos/tratamento farmacológico , Pirazinas/administração & dosagem , Administração Oral , Adulto , Idoso , Tumor Carcinoide/sangue , Tumor Carcinoide/tratamento farmacológico , Estudos de Coortes , Feminino , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Tumores Neuroendócrinos/sangue , Pirazinas/efeitos adversos , Pirazinas/sangue
18.
Pharm Dev Technol ; 24(10): 1236-1242, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31407940

RESUMO

Objective: Tanshinone IIA (TSN) and Tetramethylpyrazine (TMP) were combined in a composite, oil-in-water nanoemulsions (TSN/TMP O/W NEs) was prepared to prolong in vitro and vivo circulation time, and enhance the bioavailability of TSN. Material and methods: Physicochemical characterization of TSN/TMP O/W NEs was characterized systematically. The in vitro dissolution and in vivo pharmacokinetic experiments of TSN/TMP O/W NEs were also evaluated. Result: A formulation was optimized, yielding a 32.5 nm average particle size, an encapsulation efficiency of over 95 %, and were spherical in shape as shown by TEM. TSN/TMP O/W NEs were shown to extend the release and availability in vitro compared to raw compounds. In pharmacokinetic study, the AUC0→∞ and t1/2 of the TSN/TMP O/W NEs were 481.50 mg/L*min and 346.39 min higher than TSN solution, respectively. Brain tissue concentration of TSN was enhanced with TSN/TMP O/W NEs over raw TSN and even TSN O/W NEs. Conclusions: Therefore, nanoemulsions are an effective carrier to increase encapsulation efficiency of drugs, improve bioavailability and brain penetration for TSN - which is further enhanced by pairing with the co-delivery of TMP, providing a promising drug delivery.


Assuntos
Abietanos/química , Abietanos/farmacocinética , Encéfalo/metabolismo , Composição de Medicamentos/métodos , Nanocompostos/química , Pirazinas/química , Pirazinas/farmacocinética , Abietanos/sangue , Animais , Disponibilidade Biológica , Combinação de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Emulsões , Tamanho da Partícula , Pirazinas/sangue , Ratos Sprague-Dawley , Solubilidade , Propriedades de Superfície , Distribuição Tecidual
19.
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
20.
J Pharm Biomed Anal ; 164: 509-513, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30453157

RESUMO

USFDA has approved a novel Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (ACA) for the treatment of mantle cell lymphoma in adults. ACA is more potent and selective with fewer side effects compared to other Bruton tyrosine kinase inhibitors. In the current work a highly sensitive, selective and specific LC-MS/MS method for the estimation of acalabrutinib (ACA) in rat plasma was developed. Agilent Eclipse Plus C 8 column (50 mm × 4.6 mm, µm), with gradient elution using 10 mM ammonium formate and acetonitrile as mobile phase at a flow rate of 0.6 mL/min was used for the chromatographic separation. The ion transitions were quantified in positive mode with MRM transition of 466.1→372.3 for ACA and 236.8→194.0 for internal standard (IS). Solid phase extraction process was used as sample preparation approach. The method was validated according to USFDA bioanalytical guidelines. The method provided good linearity over the range of 0.2-199.14 ng/mL for ACA with short run time of 4 min. The method offers very high sensitivity (0.2 ng/mL) and was free from matrix interferences. The validated LC-MS/MS method was successfully applied for in vivo pharmacokinetic study in Sprague Dawley rats. The Cmax of ACA was found to be 25.56 ng/mL reaching at time of 0.5 h. The developed analytical method can also be utilized for bioequivalence studies and/or for pharmacokinetic studies in clinics.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Pirazinas/farmacocinética , Extração em Fase Sólida/métodos , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Benzamidas/administração & dosagem , Benzamidas/sangue , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Masculino , Modelos Animais , Pirazinas/administração & dosagem , Pirazinas/sangue , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Extração em Fase Sólida/instrumentação , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos , Equivalência Terapêutica
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