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2.
Acta Pharm Sin B ; 9(4): 769-781, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31384537

RESUMO

Bicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus (HCV) with unknown mechanism. Here, we showed that bicyclol significantly inhibited HCV replication in vitro and in hepatitis C patients. Using bicyclol as a probe, we identified glycolipid transfer protein (GLTP) to be a novel restrictive factor for HCV replication. The GLTP preferentially bound host vesicle-associated membrane protein-associated protein-A (VAP-A) in competition with the HCV NS5A, causing an interruption of the complex formation between VAP-A and HCV NS5A. As the formation of VAP-A/NS5A complex is essential for viral RNA replication, up-regulation of GLTP by bicyclol reduced the level of VAP-A/NS5A complex and thus inhibited HCV replication. Bicyclol also exhibited an inhibition on HCV variants resistant to direct-acting antiviral agents (DAAs) with an efficacy identical to that on wild type HCV. In combination with bicyclol, DAAs inhibited HCV replication in a synergistic fashion. GLTP appears to be a newly discovered host restrictive factor for HCV replication, Up-regulation of GLTP causes spontaneous restriction of HCV replication.

3.
Biomed Pharmacother ; 116: 108976, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31103827

RESUMO

With the development of more effective direct-acting antivirals (DAAs), dual- or triple-therapy regimens represent the major strategy used to cure chronic hepatitis C virus (HCV) infection. Thus, shorter treatment duration regimens with low burden, few adverse effects and good patient adherence are urgently needed. This study theoretically demonstrates a proof-of-concept approach for shortening therapy duration by examining HCV-infected Huh7.5 cells after treatment with a high or low fixed dose of three DAAs (simeprevir + daclatasvir + sofosbuvir) for 6-15 days. The results demonstrated that HCV-infected Huh7.5 cells achieved an ultrarapid virologic response with undetectable HCV RNA and protein and were cured after treatment with the triple-therapy regimen for 15 days. When the treatment duration was shortened, virologic relapse might occur after treatment with a low fixed dose of the three DAAs for 9 days and did occur after treatment with a low fixed dose for 6 days, although HCV was below detectable levels at the end of treatment. However, virologic relapse could be avoided with treatment of a high fixed dose of the three DAAs for 9 or 6 days. Although a virologic breakthrough occurred after an intermittent treatment regimen at the low fixed dose, the high fixed dose cured HCV-positive Huh7.5 cells with intermittent treatment. In conclusion, HCV is persistently present below detectable levels in HCV-infected Huh7.5 cells for a long time after treatment, and a shortened therapy duration is associated with an increased risk of virologic relapse, but virologic relapse or breakthrough might be avoided by treatment with a combination of more highly effective DAAs.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/fisiologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Antivirais/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Quimioterapia Combinada , Hepacivirus/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Espaço Intracelular/virologia , Recidiva , Simeprevir/farmacologia , Simeprevir/uso terapêutico , Sofosbuvir/farmacologia , Sofosbuvir/uso terapêutico , Replicação Viral/efeitos dos fármacos
4.
Ann Transl Med ; 7(6): 122, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31032277

RESUMO

Background: To develop the clinical practice guidelines for the treatment of sepsis with traditional Chinese medicine (TCM) therapy alone or TCM combined with antibiotics. Methods: The methods and process for developing the international clinical practice guidelines were fully consulted between a group of doctors. A total of 25 experts from 14 units were involved in the development of this guideline. The major clinical questions that needed to be solved were raised first, and the best available evidence to solve them was researched. Finally, according to the principle set by the GRADE system, the available evidence was graded with levels ranging from high to low. This formed the recommendation strengths, which included strong recommendation and weak recommendation, or an expert consensus recommendation. Results: The guideline identified the terms and definition for sepsis. For example, it identified its epidemiological characters, the advantages of TCM treatment on sepsis, the diagnosis and its features, the complications, and its rehabilitation and health maintenance. The guideline has put forward 14 recommendations, among which 4 were strong recommendations and 6 were weak recommendations, in addition to 4 expert consensus recommendations. Conclusions: The methods and processes for developing international clinical practice guidelines were fully consulted under the guide of relevant laws and regulations, and relevant technical documents. Based on the best existing evidence, and combined with the characteristics of TCM and the clinical realities, we developed Clinical practice guidelines for the treatment of sepsis with TCM therapy alone or TCM combined with antibiotics, with full reference to the experts' experience and patients' preferences.

5.
Eur J Pharmacol ; 853: 111-120, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30902657

RESUMO

Farnesoid X receptor (FXR) agonists play important regulatory roles in bile acid, lipid and glucose metabolism in vitro and in vivo. Thus, FXR agonists exhibit potential therapeutic effects on metabolism-related diseases that are associated with extrahepatic manifestations induced by hepatitis C virus (HCV) infection. This study investigated the effect and mechanism of FXR agonist GW4064 against HCV in vitro to explore the potential application of FXR agonists. Results showed that GW4064 and other FXR agonists have potent antiviral activity against HCV in Huh7.5 cells. GW4064 down-regulated the expression of scavenger receptor class B type I protein via FXR and thereby indirectly inhibited HCV entry into cells, leading to interruption of HCV life cycle. GW4064 also exhibited synergistic anti-HCV effect with known direct-acting antiviral agents (DAAs) used in the clinic and remained sensitive to DAA-resistant HCV mutations. Therefore, FXR agonists are also a kind of antiviral agent, and might be helpful in treatment of HCV-induced hepatic and extrahepatic manifestations.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Isoxazóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Depuradores Classe B/genética , Internalização do Vírus/efeitos dos fármacos , Antivirais/farmacologia , Linhagem Celular , Sinergismo Farmacológico , Hepacivirus/genética , Humanos , Mutação , RNA Viral/biossíntese , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Virais/metabolismo
6.
J Cell Physiol ; 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30779115

RESUMO

Polycystic ovary syndrome (PCOS) is one of the most prevalent reproductive disorders in women worldwide. Despite rigorous research, the exact molecular mechanism that governs PCOS pathogenesis remains unclear. To investigate the potential roles of circular RNAs (circRNAs), this study sequenced ribosomal RNA-depleted total RNA from exosomes of follicle fluids obtained from PCOS patients using non-PCOS samples as controls. Bioinformatic analysis identified 167 upregulated and 245 downregulated circRNAs from a total of 16,771 detected candidates. Functional analysis suggests that pathways related to bacterial infection, associated chronic inflammation, and oxidative stress could be targeted by the differential circRNAs in PCOS patients. The obtained sequencing results were further validated by quantitative reverse-transcription polymerase chain reaction and a circRNA-microRNA interaction network was constructed. The obtained results provide a valuable addition to the published studies on the mechanism of PCOS pathogenesis by revealing a wide variety of new circRNAs, miRNA, and gene targets that merit further investigation.

7.
Luminescence ; 34(3): 334-340, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30734468

RESUMO

We present an innovative and sensitive electrogenerated chemiluminescence (ECL) strategy for observing the surface feature of a single silica nanoparticle based on its collision with an ultramicroelectrode (UME). As an ECL luminophore, Ru(bpy)3 2+ molecules are doped into silica nanoparticles. The stochastic collision events of Ru(bpy)3 2+ -doped silica nanoparticles (RuSNPs) can be tracked by observing the ECL 'blips' from the ECL reaction of Ru(bpy)3 2+ with a coreactant in solution. When RuSNPs collided with UME, Ru(bpy)3 2+ molecules that only exist near the collision site of silica nanoparticles (NPs) were electrochemically oxidized to form Ru(bpy)3 3+ , and then emitted light, because silica NPs are insulated. The inhomogeneous properties of silica nanoparticle surfaces will produce diverse ECL blips in intensity and shape. In addition, distribution gradients from the he Ru(bpy)3 2+ in a silica matrix also affect ECL blips. Some information on the surface properties of silica NPs can be obtained by observation of single silica collision events.


Assuntos
Técnicas Eletroquímicas/instrumentação , Nanopartículas/química , Rutênio/química , Dióxido de Silício/química , Eletrodos , Luminescência , Propriedades de Superfície
8.
Eur J Med Chem ; 143: 1053-1065, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29232582

RESUMO

Aloperine (1), a Chinese natural product with a unique endocyclic scaffold, was first identified to be a potent hepatitis C virus (HCV) inhibitor in our laboratory. Thirty-four new aloperine derivatives were designed, synthesized and evaluated for their anti-HCV activities taking 1 as the lead. Among them, compound 7f exhibited the potential potency with EC50 values in a micromolar range against both wild-type and direct-acting antiviral agents (DAAs)-resistant variants, and synergistically inhibited HCV replication with approved DAAs. Furthermore, it also owned a good oral pharmacokinetic and safety profile, suggesting a highly druglike nature. The primary mechanism showed that 7f might target host components, distinctly different from the DAAs currently used in clinic. Therefore, we consider aloperine derivatives to be a novel class of anti-HCV agents, and compound 7f has been selected as a promising antiviral candidate for further investigation.


Assuntos
Antivirais/farmacologia , Desenho de Drogas , Hepacivirus/efeitos dos fármacos , Piperidinas/farmacologia , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/administração & dosagem , Piperidinas/química , Relação Estrutura-Atividade , Fatores de Tempo , Replicação Viral/efeitos dos fármacos
9.
Front Pharmacol ; 9: 1438, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30618739

RESUMO

Treatment with direct-acting antivirals (DAAs) cures most patients infected with hepatitis C virus (HCV) in the real world. However, some patients, especially those with the underlying advanced liver disease, have a limited reduction of liver injury after achieving a sustained viral response (SVR). Bicyclol was widely used in clinics for the treatment of a variety of liver injuries but with an unknown mechanism for the treatment of hepatitis C. We investigated the anti-inflammatory effects and mechanisms of bicyclol in HCV-infected hepatocytes and further confirmed the putative results in a mouse hepatitis model induced by the coinjection of polyinosinic-polycytidylic acid [poly (I:C)] and D-galactosamine (D-GalN). The results showed that the activation of nuclear factor kappa B (NF-κB) and the subsequent increase of inflammatory factors were directly induced by HCV infection and were persistent after clearance of the virus in Huh7.5 cells. Bicyclol decreased the activation of NF-κB and the levels of inflammatory factors in HCV-infected hepatocytes by inhibiting the activation of the ROS-MAPK-NF-κB pathway, and the effect was synergistic with DAAs in HCV-infected hepatocytes. Bicyclol attenuated the ROS-MAPK-NF-κB axis via recovering mitochondrial function without a dependence on dihydronicotinamide adenine dinucleotide phosphate oxidase and superoxide dismutases. The anti-inflammatory effects and mechanism of bicyclol were verified in mouse hepatitis induced by the coinjection of poly(I:C)/D-GalN. Bicyclol directly ameliorates the chronic inflammation caused by HCV infection and might be used with DAAs or after DAA therapy for ultimately curing chronic hepatitis C.

10.
Sci Rep ; 7(1): 14828, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29093517

RESUMO

The terahertz (THz) modulator, which will be applied in next-generation wireless communication, is a key device in a THz communication system. Current THz modulators based on traditional semiconductors and metamaterials have limited modulation depth or modulation range. Therefore, a THz modulator based on annealed tungsten disulfide (WS2, p-type) and high-resistivity silicon (n-type) is demonstrated. Pumped by a laser, the modulator presents a laser power-dependent modulation effect. Ranging from 0.25 to 2 THz, the modulation depth reaches 99% when the pumping laser is 2.59 W/cm2. The modulator works because the p-n heterojunction can separate and limit carriers to change the conductivity of the device, which results in a modulation of the THz wave. The wide band gap of WS2 can promote the separation and limitation of carriers to obtain a larger modulation depth, which provides a new direction for choosing new materials and new structures to fabricate a better THz modulator.

11.
Int J Mol Med ; 40(6): 1792-1802, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29039494

RESUMO

The hepatitis C virus (HCV) infection is associated with various extrahepatic manifestations, which are correlated with poor outcomes, and thus increase the morbidity and mortality of chronic hepatitis C (CHC). Therefore, understanding the internal linkages between systemic manifestations and HCV infection is helpful for treatment of CHC. Yet, the mechanism by which the virus evokes the systemic diseases remains to be elucidated. In the present study, using gene set enrichment analysis (GSEA) and signaling pathway impact analysis (SPIA), a comprehensive analysis of microarray data of mRNAs was conducted in HCV-infected and -uninfected Huh7.5 cells, and signaling pathways (which are significantly activated or inhibited) and certain molecules (which are commonly important in those signaling pathways) were selected. Forty signaling pathways were selected using GSEA, and eight signaling pathways were selected with SPIA. These pathways are associated with cancer, metabolism, environmental information processing and organismal systems, which provide important information for further clarifying the intrinsic associations between syndromes of HCV infection, of which seven pathways were not previously reported, including basal transcription factors, pathogenic Escherichia coli infection, shigellosis, gastric acid secretion, dorso-ventral axis formation, amoebiasis and cholinergic synapse. Ten genes, SOS1, RAF1, IFNA2, IFNG, MTHFR, IGF1, CALM3, UBE2B, TP53 and BMP7 whose expression may be the key internal driving molecules, were selected using the online tool Anni 2.1. Furthermore, the present study demonstrated the internal linkages between systemic manifestations and HCV infection, and presented the potential molecules that are key to those linkages.


Assuntos
Hepacivirus/fisiologia , Hepacivirus/patogenicidade , Hepatite C/metabolismo , Hepatite C/fisiopatologia , Interações Hospedeiro-Patógeno/fisiologia , Transdução de Sinais/fisiologia , Algoritmos , Linhagem Celular , Biologia Computacional , Infecções por Escherichia coli , Regulação da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Transcrição
12.
Biomed Res Int ; 2017: 1236801, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28904942

RESUMO

Use of direct-acting antivirals sometimes causes viral drug resistance, resulting in inefficiency in treated patients in real-world practice. Therefore, how to rapidly and accurately evaluate drug resistance is an urgent problem to be solved for rational use and development of antivirals in the future. Here, we aim to develop a new method by which we can evaluate easily but effectively whether a drug will still be efficient in the future treatment in infectious hepatitis C virus cell culture system. HCV-infected Huh7.5 cells were treated with drugs and the culture supernatants were replaced with fresh culture media containing the same drugs at 24 hours. The supernatants were harvested at 48 hours and incubated with naïve Huh7.5 cells. Intracellular HCV RNAs or proteins in the newly infected cells were extracted and analyzed at 48 hours or longer. Results showed that after being treated with telaprevir mutant viruses were easily detected which were resistant to telaprevir, while after being treated with sofosbuvir drug-resistant viruses did not emerge. In conclusion, the new method is simple and quick but accurate to evaluate whether a drug will be still efficient in the forthcoming therapeutic regimen and whether drug resistance will occur after long-term treatment with drugs.


Assuntos
Farmacorresistência Viral/genética , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Antivirais/farmacologia , Linhagem Celular , Farmacorresistência Viral/efeitos dos fármacos , Genótipo , Hepacivirus/patogenicidade , Hepatite C/virologia , Humanos , Oligopeptídeos/farmacologia , Proteínas não Estruturais Virais/genética
13.
Sci Rep ; 7(1): 8616, 2017 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-28819219

RESUMO

GBR is currently accepted as one of the most effective approaches for bone defect regeneration relating to dental implant. Icariin is the main active ingredient in the extraction of total flavonoids from the Chinese traditional herb Epimediumbrevicornum Maxim. In this study, ICA was successfully incorporated into the nanofibers barrier membrane (ICA-SF/PLCL) as osteoinduction factor by coaxial electrospinning and was released in a sustained and controlled manner. The entire release period included two stages: an initial burst stage (47.54 ± 0.06% on 5 d) and a decreasing and constant stage (82.09 ± 1.86% on 30 d). The membrane has good biocompatibility with BMMSCs anchored and significantly promoted its osteogenic activity. Moreover, in vivo experiment, bone defect covered by ICA-SF/PLCL membrane in rat cranium were statistically repaired compare to other groups. 12 weeks after implantation, in the test group, the new bone formation spread to cover most of the defect region with volume and density of approximately 15.95 ± 3.58 mm3 and 14.02 ± 0.93%. These results demonstrated that ICA-SF/PLCL nanofibrous membrane could be a promising barrier applicated for GBR.


Assuntos
Materiais Biocompatíveis/química , Regeneração Óssea/fisiologia , Membranas Artificiais , Nanofibras/química , Animais , Materiais Biocompatíveis/farmacologia , Regeneração Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Técnicas Eletroquímicas/métodos , Feminino , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Nanofibras/ultraestrutura , Osteogênese/efeitos dos fármacos , Ratos Sprague-Dawley , Crânio/efeitos dos fármacos , Crânio/fisiologia , Engenharia Tecidual/métodos , Tecidos Suporte/química
14.
Acta Pharmacol Sin ; 37(12): 1574-1586, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27593221

RESUMO

AIM: Honokiol (HNK) is a natural compound isolated from the magnolia plant with numerous pharmacological activities, including inhibiting epithelial-mesenchymal transition (EMT), which has been proposed as an attractive target for anti-tumor drugs to prevent tumor migration. In this study we investigated the effects of HNK on EMT in human NSCLC cells in vitro and the related signaling mechanisms. METHODS: TNF-α (25 ng/mL) in combination with TGF-ß1 (5 ng/mL) was used to stimulate EMT of human NSCLC A549 and H460 cells. Cell proliferation was analyzed using a sulforhodamine B assay. A wound-healing assay and a transwell assay were performed to examine cell motility. Western blotting was used to detect the expression levels of relevant proteins. siRNAs were used to knock down the gene expression of c-FLIP and N-cadherin. Stable overexpression of c-FLIP L (H157-FLIP L) or Lac Z (H157-Lac Z) was also performed. RESULTS: Treatment with TNF-α+TGF-ß1 significantly enhanced the migration of A549 and H460 cells, increased c-FLIP, N-cadherin (a mesenchymal marker), snail (a transcriptional modulator) and p-Smad2/3 expression, and decreased IκB levels in the cells; these changes were abrogated by co-treatment with HNK (30 µmol/L). Further studies demonstrated that expression level of c-FLIP was highly correlated with the movement and migration of NSCLC cells, and the downstream effectors of c-FLIP signaling were NF-κB signaling and N-cadherin/snail signaling, while Smad signaling might lie upstream of c-FLIP. CONCLUSION: HNK inhibits EMT-mediated motility and migration of human NSCLC cells in vitro by targeting c-FLIP, which can be utilized as a promising target for cancer therapy, while HNK may become a potential anti-metastasis drug or lead compound.


Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Lignanas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Humanos
15.
Oncol Rep ; 34(3): 1289-300, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26136140

RESUMO

Honokiol (HNK), a potential antitumor compound, has been widely studied in recent years. It induces apoptosis and affects autophagy in cancer cells, yet the mechanism of its antitumor efficacy remains obscure. Chloroquine (CQ), an autophagy inhibitor, is often applied to sensitize antitumor drugs in clinical trials. Here, we investigated the antitumor effect of HNK or CQ alone or in combination in non-small cell lung cancer (NSCLC) cells. Using an experimental approach, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) or sulforhodamine B (SRB) was used to determine the cytotoxicity of the agents. The expression levels of proteins were detected by western blotting. Apoptosis was examined via Annexin V-FITC and PI staining. H460 cell xenografts in nude mice were used to study the effects of HNK and/or CQ in vivo. Transfection with siRNA was applied to knock down cathepsin D. The results demonstrated the enhanced effects of HNK combined with CQ on the inhibition of proliferation, induction of apoptosis in vitro and the reduction in growth in vivo. It was confirmed that HNK and/or CQ triggered apoptosis via a caspase-dependent manner. Furthermore, HNK significantly increased the expression of p62 and LC3-Ⅱ in the A549 and H460 cells and inhibited autophagy and induced apoptosis in a cathepsin D-involved manner. In conclusion, an enhanced antitumor effect was demonstrated following treatment with HNK combined with CQ by inhibiting autophagy and inducing apoptosis via a caspase-dependent and cathepsin D-involved manner. This combination may be a novel and useful antitumor approach for chemotherapy in NSCLC.


Assuntos
Compostos de Bifenilo/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloroquina/administração & dosagem , Sinergismo Farmacológico , Lignanas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Proteínas de Neoplasias/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Chem Commun (Camb) ; 50(67): 9477-80, 2014 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-25007971

RESUMO

A bis-alkynylplatinum(II) terpyridine tweezer-alkynylgold(III) diphenylpyridine guest is shown to maintain the specific complexation in the presence of a B21C7-secondary ammonium salt recognition motif, which facilitates the formation of supramolecular hyperbranched polymers via the "tweezering directed self-assembly" strategy.


Assuntos
Compostos Organoplatínicos/química , Polímeros/química , Piridinas/química , Modelos Moleculares , Conformação Molecular , Polimerização
17.
Pharmazie ; 69(2): 138-41, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24640604

RESUMO

The cytochrome P450 2D6 (CYP2D6) is the most highly polymorphic isoenzyme of the cytochrome P-450-system, which affects the metabolism of one-fourth of all prescription drugs. Tramadol, a narcotic-like pain reliever used to treat moderate to severe pain, is primarily metabolized by CYP2D6. The CYP2D6*10 allele is the most common allele in the Chinese population. Therefore, we investigated the effects of CYP2D6*10 on tramadol pharmacokinetics in 45 post-operative patients who had undergone gastrointestinal tract surgery. Tramadol was administered to the patients after the operation, and the plasma concentrations of tramadol and O-desmethyltramadol were subsequently evaluated at 12 time points. Pharmacokinetic analyses were performed using non-compartmental methods. The area under the curve (AUC), plasma clearance (CL), elimination half-life (T1/2), mean residence time (MRT), peak concentration, and peak time of tramadol and O-desmethyltramadol were calculated. CYP2D6*10 was genotyped by polymerase chain reaction-restriction fragment length polymorphism. The frequency of CYP2D6*10 alleles was 51% in the 45 patients. The patients were divided into three groups according to their CYP2D6*10 genotype: wild-type, heterozygous, and homozygous mutant. Pharmacokinetic parameters were compared among the three groups. The analyses showed that T1/2, MRT, and AUC of tramadol were larger, and CL was lower in homozygous mutant patients compared to the wild-type group (P< 0.05). These results show that the CYP2D6*10 genetic polymorphism has a significant impact on the pharmacokinetics of tramadol in Chinese post-operative patients.


Assuntos
Analgésicos Opioides/farmacocinética , Citocromo P-450 CYP2D6/genética , Dor Pós-Operatória/metabolismo , Tramadol/farmacocinética , Adulto , Idoso , Analgésicos Opioides/uso terapêutico , Área Sob a Curva , Biotransformação , Cromatografia Líquida de Alta Pressão , Feminino , Trato Gastrointestinal/cirurgia , Genótipo , Meia-Vida , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico , Polimorfismo Genético/genética , Tramadol/análogos & derivados , Tramadol/sangue , Tramadol/uso terapêutico
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