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1.
Eur J Drug Metab Pharmacokinet ; 47(1): 57-67, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34635990

RESUMO

BACKGROUND AND OBJECTIVES: Huanglian-Houpo decoction (HH), which is recorded in the famous traditional Chinese medicine monograph "Puji Fang," contains two individual herbs, Huanglian (Rhizoma coptidis) and Houpo (Magnoliae officinalis cortex). It was regularly used to treat seasonal epidemic colds and influenzas in ancient China. Our laboratory discovered that HH has a significant anti-H1N1 influenza virus effect. However, no pharmacokinetic and pharmacodynamic data concerning the anti-H1N1 influenza virus activity of HH are available to date. In the current study, the concentration-time profiles of two major components of HH, berberine and magnolol, in rat plasma were investigated. METHODS: An integrate pharmacokinetic approach was developed for evaluating the holistic pharmacokinetic characteristics of berberine and magnolol from HH. Additionally, the inhibition rate and levels of IFN-ß in MDCK cells infected by influenza virus were analyzed. Data were calculated using 3p97 with pharmacokinetic analysis. RESULTS: The estimated pharmacokinetic parameters were maximum plasma concentration (Cmax) 0.9086 µg/ml, area under the concentration-time curve (AUC) 347.74 µg·min/ml, and time to reach Cmax (Tmax) 64.69 min for berberine and Cmax = 0.9843 µg/ml, AUC= 450.64 µg·min/ml, Tmax = 56.86 min for magnolol, respectively. Furthermore, integrated pharmacokinetic and pharmacodynamic analysis showed that the highest plasma concentration, inhibition rate and interferon-ß (IFN-ß) secretion of HH first increased and then weakened over time, reaching their peaks at 60 min. The plasma concentration of HH is directly related to the anti-influenza virus effect. CONCLUSION: The results indicated that berberine and magnolol are the main active ingredients of HH related to its anti-influenza virus effect, which is related to the improvement of IFN-ß secretion.


Assuntos
Antivirais/farmacologia , Berberina/farmacologia , Compostos de Bifenilo/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Lignanas/farmacologia , Animais , Antivirais/sangue , Antivirais/farmacocinética , Área Sob a Curva , Berberina/sangue , Berberina/farmacocinética , Compostos de Bifenilo/sangue , Compostos de Bifenilo/farmacocinética , China , Medicamentos de Ervas Chinesas/farmacocinética , Humanos , Influenza Humana/tratamento farmacológico , Lignanas/sangue , Lignanas/farmacocinética , Masculino , Modelos Animais , Fitoterapia , Ratos , Ratos Endogâmicos
2.
Sci Rep ; 11(1): 15448, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326377

RESUMO

Herpes simplex virus is among the most prevalent sexually transmitted infections. Acyclovir is a potent, selective inhibitor of herpes viruses and it is indicated for the treatment and management of recurrent cold sores on the lips and face, genital herpes, among other diseases. The problem of the oral bioavailability of acyclovir is limited because of the low permeability across the gastrointestinal membrane. The use of nanoparticles of pseudoboehmite as a drug delivery system in vitro assays is a promising approach to further the permeability of acyclovir release. Here we report the synthesis of high purity pseudoboehmite from aluminium nitrate and ammonium hydroxide containing nanoparticles, using the sol-gel method, as a drug delivery system to improve the systemic bioavailability of acyclovir. The presence of pseudoboehmite nanoparticles were verified by infrared spectroscopy, transmission electron microscopy, and X-ray diffraction techniques. In vivo tests were performed with Wistar rats to compare the release of acyclovir, with and without the addition of pseudoboehmite. The administration of acyclovir with the addition of pseudoboehmite increased the drug content by 4.6 times in the plasma of Wistar rats after 4 h administration. We determined that the toxicity of pseudoboehmite is low up to 10 mg/mL, in gel and the dried pseudoboehmite nanoparticles.


Assuntos
Aciclovir/administração & dosagem , Hidróxido de Alumínio/química , Óxido de Alumínio/química , Antivirais/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanogéis/química , Aciclovir/sangue , Aciclovir/farmacocinética , Administração Oral , Hidróxido de Alumínio/farmacologia , Óxido de Alumínio/farmacologia , Animais , Antivirais/sangue , Antivirais/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Herpes Simples/tratamento farmacológico , Herpes Simples/virologia , Humanos , Modelos Animais , Ratos , Ratos Wistar , Simplexvirus/efeitos dos fármacos
3.
J Steroid Biochem Mol Biol ; 193: 105424, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31302219

RESUMO

Oxysterols are cholesterol oxidation derivatives. Those containing an additional hydroxyl group on the side chain of the cholesterol molecule result from a physiological enzymatic synthesis and include the majority of oxysterols present in the circulation. Among these, 25-hydroxycholesterol (25OHC) and 27-hydroxycholesterol (27OHC) are characterized by a broad antiviral activity and are now considered involved in the innate immune response against viruses. Despite the emerging role of these sterols in the innate antiviral defences, no data are available on their presence in human breast milk (BM) to date. In this study, we investigated the content of oxysterols of enzymatic synthesis in BM of twelve donor mothers at different stages of lactation (i.e. in colostrum, transitional milk, and mature milk) by gas chromatography-mass spectrometry analysis. The side-chain oxysterols 25OHC, 27OHC, and 24S-hydroxycholesterol (24SOHC) were actually present in BM in all stages of lactation, but the concentration of 27OHC showed a remarkable peak in colostrum. Antiviral assays revealed that all the colostrum samples contained 27OHC concentrations that were active in vitro against two relevant pediatric viral pathogens: the human rotavirus and the human rhinovirus. Overall, this study discloses new antiviral components of BM and suggests a passive transfer of these protective factors to the infant via breastfeeding, especially in the first few days of lactation.


Assuntos
Antivirais/análise , Leite Humano/química , Oxisteróis/análise , Adulto , Animais , Antivirais/sangue , Antivirais/farmacologia , Linhagem Celular , Chlorocebus aethiops , Colostro/química , Feminino , Humanos , Lactação , Oxisteróis/sangue , Oxisteróis/farmacologia , Rhinovirus/efeitos dos fármacos , Rotavirus/efeitos dos fármacos
4.
Artigo em Inglês | MEDLINE | ID: mdl-30373792

RESUMO

Artesunate (AS), a semisynthetic artemisinin approved for malaria therapy, inhibits human cytomegalovirus (HCMV) replication in vitro, but therapeutic success in humans has been variable. We hypothesized that the short in vivo half-life of AS may contribute to the different treatment outcomes. We tested novel synthetic ozonides with longer half-lives against HCMV in vitro and mouse cytomegalovirus (MCMV) in vivo Screening of the activities of four ozonides against a pp28-luciferase-expressing HCMV Towne recombinant identified OZ418 to have the best selectivity; its effective concentration inhibiting viral growth by 50% (EC50) was 9.8 ± 0.2 µM, and cytotoxicity in noninfected human fibroblasts (the concentration inhibiting cell growth by 50% [CC50]) was 128.1 ± 8.0 µM. In plaque reduction assays, OZ418 inhibited HCMV TB40 in a concentration-dependent manner as well as a ganciclovir (GCV)-resistant HCMV isolate. The combination of OZ418 and GCV was synergistic in HCMV inhibition in vitro Virus inhibition by OZ418 occurred at an early stage and was dependent on the cell density at the time of infection. OZ418 treatment reversed HCMV-mediated cell cycle progression and correlated with the reduction of HCMV-induced expression of pRb, E2F1, and cyclin-dependent kinases 1, 2, 4, and 6. In an MCMV model, once-daily oral administration of OZ418 had significantly improved efficacy against MCMV compared to that of twice-daily oral AS. A parallel pharmacokinetic study with a single oral dose of OZ418 or AS showed a prolonged plasma half-life and higher unbound concentrations of OZ418 than unbound concentrations of AS. In summary, ozonides are proposed to be potential therapeutics, alone or in combination with GCV, for HCMV infection in humans.


Assuntos
Antivirais/farmacologia , Infecções por Citomegalovirus/tratamento farmacológico , Citomegalovirus/efeitos dos fármacos , Compostos Heterocíclicos com 1 Anel/farmacologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Compostos de Espiro/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/sangue , Antivirais/química , Antivirais/farmacocinética , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Linhagem Celular , Citomegalovirus/genética , Citomegalovirus/metabolismo , Infecções por Citomegalovirus/virologia , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibroblastos/virologia , Ganciclovir/farmacologia , Regulação da Expressão Gênica , Compostos Heterocíclicos com 1 Anel/sangue , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacocinética , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Compostos de Espiro/sangue , Compostos de Espiro/química , Compostos de Espiro/farmacocinética
5.
Artigo em Inglês | MEDLINE | ID: mdl-30373799

RESUMO

NVR 3-778 is the first capsid assembly modulator (CAM) that has demonstrated antiviral activity in hepatitis B virus (HBV)-infected patients. NVR 3-778 inhibited the generation of infectious HBV DNA-containing virus particles with a mean antiviral 50% effective concentration (EC50) of 0.40 µM in HepG2.2.15 cells. The antiviral profile of NVR 3-778 indicates pan-genotypic antiviral activity and a lack of cross-resistance with nucleos(t)ide inhibitors of HBV replication. The combination of NVR 3-778 with nucleos(t)ide analogs in vitro resulted in additive or synergistic antiviral activity. Mutations within the hydrophobic pocket at the dimer-dimer interface of the core protein could confer resistance to NVR 3-778, which is consistent with the ability of the compound to bind to core and to induce capsid assembly. By targeting core, NVR 3-778 inhibits pregenomic RNA encapsidation, viral replication, and the production of HBV DNA- and HBV RNA-containing particles. NVR 3-778 also inhibited de novo infection and viral replication in primary human hepatocytes with EC50 values of 0.81 µM against HBV DNA and between 3.7 and 4.8 µM against the production of HBV antigens and intracellular HBV RNA. NVR 3-778 showed favorable pharmacokinetics and safety in animal species, allowing serum levels in excess of 100 µM to be achieved in mice and, thus, enabling efficacy studies in vivo The overall preclinical profile of NVR 3-778 predicts antiviral activity in vivo and supports its further evaluation for safety, pharmacokinetics, and antiviral activity in HBV-infected patients.


Assuntos
Antivirais/farmacologia , Benzamidas/farmacologia , Capsídeo/efeitos dos fármacos , DNA Viral/antagonistas & inibidores , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Piperidinas/farmacologia , RNA Viral/antagonistas & inibidores , Animais , Antígenos Virais/genética , Antígenos Virais/metabolismo , Antivirais/sangue , Antivirais/química , Antivirais/farmacocinética , Benzamidas/sangue , Benzamidas/química , Benzamidas/farmacocinética , Capsídeo/química , Capsídeo/metabolismo , DNA Viral/genética , DNA Viral/metabolismo , Avaliação Pré-Clínica de Medicamentos , Feminino , Células Hep G2 , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Hepatócitos/virologia , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Piperidinas/sangue , Piperidinas/química , Piperidinas/farmacocinética , Cultura Primária de Células , RNA Viral/genética , RNA Viral/metabolismo , Proteínas do Core Viral/antagonistas & inibidores , Proteínas do Core Viral/genética , Proteínas do Core Viral/metabolismo , Replicação Viral/efeitos dos fármacos
6.
Clin Drug Investig ; 38(11): 1053-1060, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30203386

RESUMO

BACKGROUND AND OBJECTIVE: Baloxavir marboxil is a prodrug that is metabolized to baloxavir acid, which suppresses viral replication by inhibiting cap-dependent endonuclease with a single oral administration. As the mode of action of baloxavir marboxil is different from that of neuraminidase inhibitors, such as oseltamivir, combination treatment with these drugs can be a treatment option, particularly for severe influenza infection. The aim of this study was to assess the drug-drug interaction between baloxavir marboxil and oseltamivir. METHODS: Eighteen healthy adult subjects received three treatments in a crossover fashion: single administration of baloxavir marboxil 40 mg alone, repeated twice-daily administration of oseltamivir at 75 mg for 5 days, or single administration of baloxavir marboxil at 40 mg in combination with repeated twice-daily administration of oseltamivir at 75 mg for 5 days. RESULTS: The ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve of baloxavir acid after co-administration compared to baloxavir marboxil alone were 1.03 (0.92-1.15) and 1.01 (0.96-1.06), respectively. The ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve of oseltamivir carboxylate, the active form of oseltamivir, after co-administration compared to oseltamivir alone were 0.96 (0.93-1.00) and 0.99 (0.96-1.01), respectively, at steady state on day 5. Treatment-emergent adverse events reported were mild and not considered to be related to the study drug. CONCLUSION: The lack of a clinically meaningful drug-drug interaction between baloxavir marboxil and oseltamivir has been established.


Assuntos
Oseltamivir/administração & dosagem , Oseltamivir/sangue , Pró-Fármacos/administração & dosagem , Pró-Fármacos/metabolismo , Administração Oral , Adulto , Antivirais/administração & dosagem , Antivirais/sangue , Estudos Cross-Over , Avaliação Pré-Clínica de Medicamentos/métodos , Interações Medicamentosas/fisiologia , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/sangue , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
Clin Pharmacokinet ; 57(8): 911-928, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29353349

RESUMO

Daclatasvir is a first-in-class, highly selective, hepatitis C virus, non-structural protein 5a polymerase replication complex inhibitor with picomolar potency and broad genotypic coverage in vitro. Daclatasvir undergoes rapid absorption, with a time to reach maximum plasma concentration of 1-2 h and an elimination half-life of ~ 10 to 14 h observed in single-ascending dose studies. Steady state was achieved by day 4 in multiple-ascending dose studies. Daclatasvir can be administered without regard to food or pH modifiers. Daclatasvir exposure is similar between healthy subjects and subjects infected with hepatitis C virus. Intrinsic factors such as age, race, or sex do not impact daclatasvir exposure. No dose adjustment is necessary for patients with any degree of hepatic or renal impairment. Daclatasvir has low-to-moderate clearance with the predominant route of elimination via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion. Renal clearance is a minor route of elimination for daclatasvir. As a result, the dose of daclatasvir should be reduced from 60 to 30 mg once daily when co-administered with strong inhibitors of cytochrome P450 3A4. No dose adjustment is required when daclatasvir is co-administered with moderate inhibitors of cytochrome P450 3A4. The dose of daclatasvir should be increased from 60 to 90 mg once daily when co-administered with moderate inducers of cytochrome P450 3A4. Co-administration of daclatasvir with strong inducers of cytochrome P450 3A4 is contraindicated. Concurrent medications with inhibitory effects on P-glycoprotein without concurrent inhibition of cytochrome P450 3A4 are unlikely to cause marked changes in daclatasvir exposure, as the clearance of daclatasvir is through both cytochrome P450 3A4 and P-glycoprotein. The potential for daclatasvir to affect the pharmacokinetics of concomitantly administered drugs that are substrates of the cytochrome P450 enzyme system is low. In vitro, daclatasvir is a weak-to-moderate inhibitor of transporters including organic cation transporter 1, P-glycoprotein, organic transporting polypeptide 1B1, organic transporting polypeptide 1B3, and breast cancer resistance protein, although in clinical studies, daclatasvir has not altered the pharmacokinetics of concomitantly administered drugs that are substrates of these transporters to an appreciable degree, except for rosuvastatin. In summary, daclatasvir is a hepatitis C virus, non-structural protein 5a-selective inhibitor with a well-characterized pharmacokinetic profile that forms part of potent and well-tolerated all-oral treatment regimens for chronic hepatitis C virus infection.


Assuntos
Antivirais/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Imidazóis/farmacocinética , Absorção Fisiológica , Animais , Antivirais/administração & dosagem , Antivirais/sangue , Disponibilidade Biológica , Carbamatos , Ensaios Clínicos como Assunto , Citocromo P-450 CYP3A/metabolismo , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Meia-Vida , Hepatite C Crônica/sangue , Humanos , Imidazóis/administração & dosagem , Imidazóis/sangue , Pirrolidinas , Distribuição Tecidual , Valina/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores
8.
Biomed Chromatogr ; 31(8)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28052484

RESUMO

Isochlorogenic acid A is widely present in fruits, vegetables and herbal medicines, and is characterized by anti-inflammatory, hepatoprotective and antiviral properties. However, little is known about its metabolic fate and pharmacokinetic properties. This study is thus designed to investigate the metabolic fate of isochlorogenic acid A. An analytical method based on high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (HPLC/Q-TOF MS) was established to characterize the metabolites of isochlorogenic acid A in the plasma, urine and feces of rats. A total of 32 metabolites were identified. The metabolic pathways mainly include hydrolyzation, dehydroxylation, hydrogenation and conjugation with methyl, glucuronic acid, glycine, sulfate, glutathione and cysteine. Moreover, the pharmacokinetic profiles of all the circulating metabolites were investigated. M11 resulting from hydrolyzation, dehydroxylation and hydrogenation was the dominant circulating metabolite after the intragastric administration of isochlorogenic acid A. The results obtained will be useful for further study of elucidating potential bioactive metabolites which can provide better explanation of the pharmacological and/or toxicological effects of this compound.


Assuntos
Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Ácido Clorogênico/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Animais , Anti-Inflamatórios/sangue , Anti-Inflamatórios/urina , Antivirais/sangue , Antivirais/metabolismo , Antivirais/farmacocinética , Antivirais/urina , Ácido Clorogênico/sangue , Ácido Clorogênico/metabolismo , Ácido Clorogênico/farmacocinética , Ácido Clorogênico/urina , Fezes/química , Masculino , Espectrometria de Massas/métodos , Redes e Vias Metabólicas , Plantas Medicinais/metabolismo , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacocinética , Ratos , Ratos Sprague-Dawley
9.
Yao Xue Xue Bao ; 51(9): 1429-35, 2016 09.
Artigo em Chinês | MEDLINE | ID: mdl-29924533

RESUMO

Entecavir (ETV), a guanosine nucleotide antiviral agent with activity against hepatitis B virus (HBV) and Huangqi decoction (HQD) that exerts significant therapeutic effects in liver cirrhosis are used as an effective drug combination in the treatment of liver cirrhosis with HBV. Therefore, this study was designed to assess the effect of HQD on ETV pharmacokinetics in rat plasma. Spraque-Dawley (SD) rats were randomized into single- and 7-day-dose experimental groups. The ETV and ETV-HQD groups were administered ETV and a simultaneous combination of ETV and HQD, respectively while the ETV-HQD-2h group received HQD 2 h after ETV treatment, all administered via intragastric (i.g.) gavage. A rapid, sensitive, and efficient ultra-high- performance liquid chromatography-linear trap quadrupole (UHPLC-LTQ)-Orbitrap method was developed and validated to determine ETV in rat plasma from blood samples collected at different time points following treatment. The linearity, accuracy, precision, recovery, matrix effects and stability of ETV were all satisfactory. The ETV-HQD group exhibited a decrease in the maximum plasma concentration (Cmax), and a delay in time to achieve Cmax (tmax) following single- and multi-dose administrations, and decreased area under the concentration- time curve (AUC0­t) following single dosing. ETV pharmacokinetics did not change significantly between the ETV and ETV-HQD-2h groups. In vitro everted intestinal sac models experiments indicated that HQD decreased the absorption of ETV. HQD prevented ETV from accessing the intestinal mucosa epithelial surface, thereby decreasing its absorption in rats.


Assuntos
Antivirais/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Guanina/análogos & derivados , Adulto , Animais , Antivirais/sangue , Cromatografia Líquida de Alta Pressão , Guanina/sangue , Guanina/farmacocinética , Humanos , Plasma , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
10.
Arch Pharm Res ; 37(11): 1416-25, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24338503

RESUMO

Chronic hepatitis B virus (HBV) infection may lead to liver cirrhosis and hepatocellular carcinoma, but few drugs are available for its treatment. Acyclic nucleoside phosphonates (ANPs) have remarkable antivirus activities but are not easily absorbed from the gastrointestinal tract and accumulate in the kidneys, resulting in nephrotoxicity. Therefore, there is a need to find effective liver site-specific prodrugs. The dipivaloyloxymethyl ester of 9-(2-phosphonylmethoxyethyl)adenine (PMEA)-adefovir dipivoxil (ADV)-is a first-line therapy drug for chronic hepatitis B with a low therapeutic index because of renal toxicity and low hepatic uptake. In this study, a series of PMEA derivatives were synthesized to enhance plasma stability and liver release. The metabolic stability of ADV (Chemical I) and its two analogues (Chemicals II and III) was evaluated in rat plasma and liver homogenate in vitro. An ion-pair reverse-phase HPLC-UV method and a hybrid ion trap and high-resolution time-of-flight mass spectrometry (LC-IT-TOF-MS) were used to evaluate the degradation rate of the analogues and to identify their intermediate metabolites, respectively. Chemicals I and II were hydrolyzed by cleavage of the C-O bond to give monoesters. Sufficient enzymatic activation in the liver homogenate through a relatively simple metabolic pathway, in addition to a favorable stability profile in rat plasma, made Chemical II an optimal candidate. Next, six analogues based on the structure of Chemical II were synthesized and evaluated in plasma and liver homogenate. Compared to Chemical II, these compounds generated less active PMEA levels in rat liver homogenate. Therefore, chemical modification of Chemical II may lead to new promising PMEA derivatives with enhanced plasma stability and liver activation.


Assuntos
Adenina/análogos & derivados , Antivirais/sangue , Antivirais/síntese química , Vírus da Hepatite B/efeitos dos fármacos , Fígado/efeitos dos fármacos , Organofosfonatos/sangue , Organofosfonatos/síntese química , Adenina/sangue , Adenina/síntese química , Adenina/farmacologia , Animais , Antivirais/farmacologia , Biotransformação , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Ésteres , Técnicas In Vitro , Fígado/metabolismo , Estrutura Molecular , Organofosfonatos/farmacologia , Ratos , Espectrometria de Massas por Ionização por Electrospray
11.
J Pharmacol Exp Ther ; 344(2): 388-96, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23143674

RESUMO

Interspecies differences in drug metabolism have made it difficult to use preclinical animal testing data to predict the drug metabolites or potential drug-drug interactions (DDIs) that will occur in humans. Although chimeric mice with humanized livers can produce known human metabolites for test substrates, we do not know whether chimeric mice can be used to prospectively predict human drug metabolism or a possible DDI. Therefore, we investigated whether they could provide a more predictive assessment for clemizole, a drug in clinical development for the treatment of hepatitis C virus (HCV) infection. Our results demonstrate, for the first time, that analyses performed in chimeric mice can correctly identify the predominant human drug metabolite before human testing. The differences in the rodent and human pathways for clemizole metabolism were of importance, because the predominant human metabolite was found to have synergistic anti-HCV activity. Moreover, studies in chimeric mice also correctly predicted that a DDI would occur in humans when clemizole was coadministered with a CYP3A4 inhibitor. These results demonstrate that using chimeric mice can improve the quality of preclinical drug assessment.


Assuntos
Antivirais/metabolismo , Benzimidazóis/metabolismo , Fígado , Quimeras de Transplante/metabolismo , Animais , Antivirais/sangue , Antivirais/farmacocinética , Antivirais/uso terapêutico , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Meia-Vida , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatite C/enzimologia , Hepatite C/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Valor Preditivo dos Testes , Ratos , Ritonavir/metabolismo , Ritonavir/farmacocinética , Ritonavir/farmacologia , Especificidade da Espécie , Replicação Viral/efeitos dos fármacos
12.
Acta Pharmacol Sin ; 33(10): 1332-6, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22902987

RESUMO

AIM: Dehydroandrographolide succinate (DAS) is extracted from herbal medicine Andrographis paniculata (Burm f) Nees. DAS injection is used in China for the treatment of viral pneumonia and upper respiratory tract infections. The aim of this study is to investigate the pharmacokinetics and tolerance of DAS injection in healthy Chinese volunteers. METHODS: This was a single-center, randomized, single-dose, three-way crossover design study. Nine eligible subjects were randomly divided into 3 groups, and each group sequentially received 80, 160, or 320 mg of DAS infusion according to a three-way Latin square design. Plasma and urine samples were collected and determined using an LC-MS/MS method. Safety and tolerability were determined via clinical evaluation and adverse event monitoring. RESULTS: For the 80, 160, and 320 mg dose groups, the mean C(max) were 4.82, 12.85, and 26.90 mg/L, respectively, and the mean AUC(0-12) were 6.18, 16.95, and 40.65 mg·L(-1)·h, respectively. DAS was rapidly cleared, with a mean T(max) of 0.94-1.0 h and a t(1/2) of approximately 1.51-1.89 h. Approximately 10.1%-15.5% of the intravenous DAS dose was excreted unchanged in urine within 24 h in the 3 groups, and more than 90% of unchanged DAS was excreted between 0 and 4 h. The pharmacokinetic profile was similar between male and female subjects. No serious or unexpected adverse events were found during the study, but one mild adverse event (stomachache) was reported. CONCLUSION: This study shows that DAS has nonlinear pharmacokinetic characteristics. To guarantee the effective concentration, mul¬tiple small doses are recommended in clinical regimens.


Assuntos
Antivirais/efeitos adversos , Antivirais/farmacocinética , Diterpenos/efeitos adversos , Diterpenos/farmacologia , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/farmacocinética , Adolescente , Adulto , Antivirais/sangue , Antivirais/química , China , Estudos Cross-Over , Diterpenos/sangue , Diterpenos/química , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Estrutura Molecular , Fatores Sexuais , Adulto Jovem
13.
Artigo em Inglês | MEDLINE | ID: mdl-22366283

RESUMO

A simple, accurate and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitation of bentysrepinine (Y101) in rat plasma. After the addition of diphenhydramine (internal standard, IS), plasma samples were pretreated by protein precipitation. Chromatographic separation was carried out on an Atlantis(®) analytical column (4.6 mm × 100 mm, 5 µm, Waters) with methanol: 20 mM ammonium formate consisting of 1.0% formic acid (65:35, v/v) as the mobile phase at an isocratic flow rate of 0.4 mL/min for 7.5 min. The multiple reaction monitoring (MRM) transitions were performed at m/z 490.2→339.5 for Y101 and m/z 256.0→167.0 for IS on a SCIEX API 4000 mass spectrometer in the positive ion mode with electrospray ionization (ESI) source. Good linearity was achieved over the concentration range of 1-2500 ng/mL. The intra- and inter-day precisions were less than 8.3%, and the accuracy ranged from -4.0% to 2.8%. Y101 was stable during the analysis and the storage period. The pharmacokinetic profiles of Y101 at three dose levels were successfully studied for the first time in rats by this method. After single intra-gastric administration of Y101 at the doses of 25, 50 and 100 mg/kg, C(max) and AUC(0-t) were proportional to the doses given.


Assuntos
Antivirais/sangue , Benzamidas/sangue , Cromatografia Líquida/métodos , Dipeptídeos/sangue , Extratos Vegetais/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Antivirais/química , Antivirais/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Dipeptídeos/química , Dipeptídeos/farmacocinética , Estabilidade de Medicamentos , Masculino , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
14.
Zhongguo Zhong Yao Za Zhi ; 36(8): 1071-4, 2011 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-21809588

RESUMO

OBJECTIVE: The candidate anti-influenza virus serum marker of Lonicera japonica was searched by comparing the serum protein discrepancy of experimental groups. It will provide the basis for setting forth the action and mechanism of anti-influenza virus. METHOD: Two-dimensional electrophoresis (2-DE) was used to separate different experimental groups and the differences in serum protein was compared. The significantly expressed protein spots was selected for mass spectrum identification and bioinformatics analysis. RESULT: Fifteen identified points of protein have more typical differences between experimental groups. The structures were identified by MALDI-TOF-MS, and 12 functional protein component ownership were retrieved. CONCLUSION: There was significant difference between the serum protein of experimental groups Proteomic methods can be used to select and identify the serum marker. It is expected to clarify the mechanism of anti-influenza virus of L. japonica.


Assuntos
Antivirais/sangue , Antivirais/isolamento & purificação , Lonicera/química , Orthomyxoviridae/efeitos dos fármacos , Proteômica/métodos , Animais , Antivirais/farmacologia , Biomarcadores/sangue , Proteínas Sanguíneas/análise , Eletroforese em Gel Bidimensional/métodos , Masculino , Camundongos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
15.
Eksp Klin Farmakol ; 74(12): 33-5, 2011.
Artigo em Russo | MEDLINE | ID: mdl-22379880

RESUMO

Features of the immune response of children with chronic hepatitis C to the antiviral and pathogenetic therapy have been studied. It is shown that the antiviral therapy is accompanied by stimulation of the immune response as manifested by the synthesis of cytokines (IL-4, IFN-alpha, IFN-gamma) with retention of increased production of IFN-a for more than two years after the end of the course of treatment. In children that previously received interferon inductor (cycloferon) for 12 months, high level of IFN-a production is retained, which ensures antiviral protection. Phytotherapy did not influence the production of cytokines.


Assuntos
Acridinas/uso terapêutico , Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Indutores de Interferon/uso terapêutico , Interferon-alfa/uso terapêutico , Acridinas/administração & dosagem , Antivirais/administração & dosagem , Antivirais/sangue , Antivirais/imunologia , Criança , Humanos , Indutores de Interferon/administração & dosagem , Interferon-alfa/administração & dosagem , Interferon-alfa/sangue , Interferon-alfa/imunologia , Interferon gama/sangue , Interferon gama/imunologia , Interleucina-4/sangue , Interleucina-4/imunologia , Fitoterapia/métodos , Preparações de Plantas/administração & dosagem , Preparações de Plantas/uso terapêutico , Fatores de Tempo , Resultado do Tratamento
16.
Biol Pharm Bull ; 33(2): 238-43, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20118546

RESUMO

Baicalein, an extract from Scutellaria baicalensis, was evaluated for its ability to inhibit the influenza virus in vivo. Oral administration of baicalein to BALB/c mice infected with the influenza A/FM1/1/47(H1N1) virus showed significant effects in preventing death, increasing the mean time to death, inhibiting lung consolidation, and reducing the lung virus titer in a dose-dependent manner. These effects are believed to be due to baicalin, the metabolite of baicalein in the serum. At a concentration of baicalin 2 microg/ml in overlay medium, it showed significant inhibition in the plaque assay, and the mean IC(50) value of baicalin was calculated as 1.2 microg/ml in the cytopathic effect assay. Our results showed that baicalein warrants further research as a potential antiinfluenza viral agent.


Assuntos
Antivirais/uso terapêutico , Flavanonas/uso terapêutico , Flavonoides/sangue , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/crescimento & desenvolvimento , Extratos Vegetais/uso terapêutico , Animais , Antivirais/sangue , Linhagem Celular , Efeito Citopatogênico Viral/efeitos dos fármacos , Cães , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/sangue , Infecções por Orthomyxoviridae/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Scutellaria baicalensis , Ensaio de Placa Viral
17.
Science ; 327(5962): 198-201, 2010 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-19965718

RESUMO

The liver-expressed microRNA-122 (miR-122) is essential for hepatitis C virus (HCV) RNA accumulation in cultured liver cells, but its potential as a target for antiviral intervention has not been assessed. We found that treatment of chronically infected chimpanzees with a locked nucleic acid (LNA)-modified oligonucleotide (SPC3649) complementary to miR-122 leads to long-lasting suppression of HCV viremia, with no evidence of viral resistance or side effects in the treated animals. Furthermore, transcriptome and histological analyses of liver biopsies demonstrated derepression of target mRNAs with miR-122 seed sites, down-regulation of interferon-regulated genes, and improvement of HCV-induced liver pathology. The prolonged virological response to SPC3649 treatment without HCV rebound holds promise of a new antiviral therapy with a high barrier to resistance.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , MicroRNAs/antagonistas & inibidores , Pan troglodytes , Oligonucleotídeos Fosforotioatos/uso terapêutico , Animais , Antivirais/efeitos adversos , Antivirais/sangue , Quimiocina CXCL10/sangue , Colesterol/sangue , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Viral , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepacivirus/fisiologia , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Interferons/metabolismo , Fígado/metabolismo , Fígado/virologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Oligonucleotídeos , Oligonucleotídeos Fosforotioatos/efeitos adversos , Oligonucleotídeos Fosforotioatos/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Carga Viral , Viremia/tratamento farmacológico
18.
Jpn J Pharmacol ; 90(4): 304-12, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12501006

RESUMO

The influence of interferon-beta (IFN-beta) dosing time on antiviral activity was investigated in ICR male mice under light-dark cycle conditions (lights on at 07:00, off at 19:00) with food and water available ad libitum. There was a significant dosing time-dependent change in 2',5'-oligoadenylate synthetase (2',5'-OAS) activities, as an index of antiviral activity, in liver at 12 h after IFN-beta (15 MIU/kg, i.v.) injection. IFN-beta-induced 2',5'-OAS activity was more potent after the drug injection during the late dark phase. The higher antiviral effect of IFN-beta was observed when the interferon-alpha/beta receptor (IFNAR) expression in the liver increased, and the lower effect was observed when its expression decreased. IFN-beta-induced fever was more serious after IFN-beta injection from the late dark phase to the early light phase. A significant dosing time-dependent change was demonstrated for plasma IFN-beta concentrations, which showed a higher level during the light phase and a lower level during the dark phase. The dosing time-dependent change of plasma IFN-beta concentrations was not associated with that of the antiviral effect or fever induced by IFN-beta. These results suggest that selecting the most suitable dosing time of IFN-beta, associated with the 24-h rhythm of IFNAR expression in the liver, may be important to increase effectively the antiviral activity of the drug in experimental and clinical situations.


Assuntos
Antivirais/farmacologia , Ritmo Circadiano , Interferon beta/farmacologia , Receptores de Interferon/efeitos dos fármacos , 2',5'-Oligoadenilato Sintetase/metabolismo , Animais , Antivirais/administração & dosagem , Antivirais/sangue , Temperatura Corporal/efeitos dos fármacos , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Hipotálamo/metabolismo , Injeções Intravenosas , Interferon beta/administração & dosagem , Interferon beta/sangue , Isoenzimas/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos ICR , Prostaglandina-Endoperóxido Sintases/metabolismo , RNA Mensageiro/metabolismo , Receptor de Interferon alfa e beta , Receptores de Interferon/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
J Pharm Pharmacol ; 52(10): 1247-55, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11092569

RESUMO

The in-vivo anti-influenza-virus activity of Stachyflin derivatives (III and its phosphate ester, III-Phos), a new class of haemagglutinin fusion inhibitor, and the improvement of their absorption after oral or intranasal administration were studied in mice, rats, and ferrets. The absorption of III in PEG 4000 and III-Phos aqueous solution increased about three and four fold in AUC after oral administration to uninfected mice compared with that of 0.5% HPMC (hydroxypropyl-methylcellulose) suspension. Using a mouse influenza virus infection model, significant anti-influenza-virus activity was observed in infected mice treated orally with these compounds dissolved in PEG 4000 or distilled water, respectively, but not in mice treated with 0.5% HPMC. The in-vivo anti-influenza-virus activity in ferrets, a good model for influenza virus infection in man, was also studied. Although the concentration of III in plasma was above the IC50 against the influenza virus strain used for 6h after the oral administration of III in PEG 400 to uninfected ferrets, no in-vivo anti-influenza-virus activity was observed at the same dosage given 4 times daily for 3 days. The intranasal administration of III-Phos, which was expected to have a more notable in-vivo anti-influenza-virus activity, was examined. III-Phos, whose intranasal absorption had been improved by the modification of III with phosphate ester in rats, inhibited viral replication in the nasal cavity and suppressed influenza-virus-induced fever when administered intranasally to infected ferrets. This study demonstrates that intranasally administered compounds with anti-influenza-virus activity must permeate the nasal membranes to produce their anti-influenza-virus effect.


Assuntos
Antivirais/farmacocinética , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Intestino Delgado/metabolismo , Cavidade Nasal/metabolismo , Sesquiterpenos/farmacocinética , Absorção , Animais , Antivirais/sangue , Antivirais/química , Avaliação Pré-Clínica de Medicamentos , Furões , Humanos , Vírus da Influenza A/metabolismo , Influenza Humana/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/sangue , Sesquiterpenos/química
20.
Am J Vet Res ; 60(7): 888-94, 1999 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10407485

RESUMO

OBJECTIVE: To determine pharmacokinetics of single and multiple doses of rimantadine hydrochloride in horses and to evaluate prophylactic efficacy of rimantadine in influenza virus-infected horses. ANIMALS: 5 clinically normal horses and 8 horses seronegative to influenza A. PROCEDURE: Horses were given rimantadine (7 mg/kg of body weight, i.v., once; 15 mg/kg, p.o., once; 30 mg/kg, p.o., once; and 30 mg/kg, p.o., q 12 h for 4 days) to determine disposition kinetics. Efficacy in induced infections was determined in horses seronegative to influenza virus A2. Rimantadine was administered (30 mg/kg, p.o., q 12 h for 7 days) beginning 12 hours before challenge-exposure to the virus. RESULTS: Estimated mean peak plasma concentration of rimantadine after i.v. administration was 2.0 micrograms/ml, volume of distribution (mean +/- SD) at steady-state (Vdss) was 7.1 +/- 1.7 L/kg, plasma clearance after i.v. administration was 51 +/- 7 ml/min/kg, and beta-phase half-life was 2.0 +/- 0.4 hours. Oral administration of 15 mg of rimantadine/kg yielded peak plasma concentrations of < 50 ng/ml after 3 hours; a single oral administration of 30 mg/kg yielded mean peak plasma concentrations of 500 ng/ml with mean bioavailability (F) of 25%, beta-phase half-life of 2.2 +/- 0.3 hours, and clearance of 340 +/- 255 ml/min/kg. Multiple doses of rimantadine provided steady-state concentrations in plasma with peak and trough concentrations (mean +/- SEM) of 811 +/- 97 and 161 +/- 12 ng/ml, respectively. Rimantadine used prophylactically for induced influenza virus A2 infection was associated with significant decreases in rectal temperature and lung sounds. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of rimantadine to horses can safely ameliorate clinical signs of influenza virus infection.


Assuntos
Antivirais/farmacocinética , Doenças dos Cavalos/tratamento farmacológico , Infecções por Orthomyxoviridae/veterinária , Orthomyxoviridae/efeitos dos fármacos , Rimantadina/farmacocinética , Administração Oral , Animais , Anticorpos Antivirais/sangue , Antivirais/administração & dosagem , Antivirais/sangue , Antivirais/normas , Área Sob a Curva , Disponibilidade Biológica , Embrião de Galinha , Feminino , Cromatografia Gasosa-Espectrometria de Massas/veterinária , Testes de Inibição da Hemaglutinação/veterinária , Doenças dos Cavalos/virologia , Cavalos , Injeções Intravenosas/veterinária , Testes de Sensibilidade Microbiana , Mucosa Nasal/virologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Rimantadina/administração & dosagem , Rimantadina/sangue , Rimantadina/normas
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