RESUMO
An efficient and reliable method using LC-MS/MS was established and validated for the simultaneous quantification of meropenem and imipenem in rat plasma. An electronic spray ion source in the positive multiple reaction monitoring mode was used for the detection and the transitions were m/z 384.6 â m/z 141.2 for meropenem, m/z 300.1 â m/z 141.8 for imipenem and m/z 423.4 â m/z 207.1 for matrine (IS). The calibration curves of meropenem and imipenem were linear in the range of 0.50-200 µg/mL. Satisfactory separation was achieved with a total run time of 3.0 min, the injection volume was 3 µl. The retention times of meropenem, imipenem and IS were 1.19, 1.14 and 1.13 min, respectively. Meropenem and imipenem are easily hydrolyzed in plasma. HEPES was used as a stabilizer and added to the plasma samples immediately after centrifugation. Extractions of meropenem, imipenem and IS were carried out by protein precipitation with acetonitrile. The specificity, precision and accuracy, stability, recovery and matrix effects were within acceptance limits. This method was successfully applied to investigate the pharmacokinetics of intravenous injection of meropenem and imipenem single administration or combined with sulbactam in rats. We found that sulbactam has no influence on the pharmacokinetics behavior of meropenem or imipenem.
Assuntos
Cromatografia Líquida/métodos , Imipenem , Meropeném , Espectrometria de Massas em Tandem/métodos , Animais , Imipenem/sangue , Imipenem/química , Imipenem/farmacocinética , Modelos Lineares , Masculino , Meropeném/sangue , Meropeném/química , Meropeném/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND Bupropion (BUP) is an antidepressant and its pharmacological activity is mediated by its major metabolite, hydroxybupropion (HBUP). We investigated the effects of genetic polymorphisms of CYP2B6 on BUP and HBUP to provide certain evidence on the clinical rational administration of BUP. MATERIAL AND METHODS Plasma BUP and HBUP concentrations were assayed using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS A total of 23 healthy volunteers (eleven participants with CYP2B6*1/*1, 7 participants with CYP2B6*1/*6, 3 participants with CYP2B6*4/*6, and 2 participants with CYP2B6*1/*4) received orally administered 150 mg of BUP according to protocol. Blood samples were obtained up to 96 hours after administration. The whole blood was subject to genotyping by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The concentration-time curve (AUC(0â96)), maximum plasma concentration (Cmax), and terminal half-life (t1/2) values of BUP in CYP2B6*1/*4 were lower than those of CYP2B6*1/*1. By contrast, the time to Cmax (tmax) value of the former was higher than that of the latter. The HBUP AUC(0â96) values in CYP2B6*4/*6 and CYP2B6*1/*4 increased to values 1.12-fold and 1.98-fold, compared with CYP2B6*1/*1 carriers. However, the HBUP AUC(0â96) value in CYP2B6*1/*1 was 1.51-fold higher than that in CYP2B6*1/*6. Similarly, the HBUP Cmax values in CYP2B6*4/*6 and CYP2B6*1/*4 increased by 1.12-fold and 1.97-fold, whereas the HBUP Cmax value in CYP2B6*1/*6 decreased to a value 1.64-fold lower than that in CYP2B6*1/*1. CONCLUSIONS Genetic polymorphisms of CYP2B6 influence the pharmacokinetic parameters of BUP and HBUP and thus establish rational BUP administration for Chinese patients in clinical settings.
Assuntos
Bupropiona/análogos & derivados , Bupropiona/farmacocinética , Citocromo P-450 CYP2B6/genética , Adolescente , Adulto , Área Sob a Curva , Povo Asiático/genética , Bupropiona/sangue , China , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Citocromo P-450 CYP2B6/metabolismo , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
In this study, we used a self-contrast method, which excluded the individual difference, to evaluate the inhibitory effect of chrysosplentin (CHR) in the presence or absence of artemisinin (ART) on the P-glycoprotein (P-gp) transport activity. A sensitive and rapid UHPLC-MS/MS method was applied for quantification of digoxin, a P-gp-specific substrate, in rat plasma. A pharmacokinetic study was carried out: first after an oral administration of digoxin at a dose of 0.09 mg/kg (first period), followed by a 20-day wash-out, then after another administration of digoxin (second period). During the second period, test compounds were orally given three times per day for seven consecutive days. Results showed that the t1/2 of digoxin in all the groups had no significant difference between the first and second periods. The AUC0-24 , Cmax , tmax , and Clz /F of the negative control and ART alone groups showed no difference. However, the AUC0-24 and Cmax in the CHR alone, CHR-ART (1:2) and verapamil (positive control) groups showed 2.34-, 3.04-, 1.79-, and 1.81-, 1.99-, 2.06-fold increases along with 3.50-, 3.84- and 4.76-fold decreases for CLz /F, respectively. The tmax in the CHR-ART (1:2) group increased 3.73-fold. In conclusion, our self-contrast study suggested that CHR, especially when combined with ART in a ratio of 1:2, inhibited P-gp activity while ART alone has no effect. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Artemisininas/farmacologia , Digoxina/metabolismo , Flavonoides/farmacologia , Animais , Área Sob a Curva , Artemisininas/farmacocinética , Transporte Biológico , Cromatografia Líquida de Alta Pressão , Digoxina/administração & dosagem , Flavonoides/farmacocinética , Masculino , Ratos , Ratos Sprague-Dawley , Padrões de Referência , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Artemisinin (ART) is an efficacious and safe anti-malarial drugs but has low oral bioavailability and auto-induction profiles during multiple dosing. The pharmacokinetic disadvantages have been found to partially depend on the induction of cytochrome P-450 enzymes by ART and resulted in the therapeutic failure due to insufficient drug levels. The present study, therefore, investigated the impacts of chrysosplenetin (CHR), a polymethoxylated flavonoid from Artemisia annua, on the pharmacokinetics and the anti-malarial efficacy of ART against Plasmodium berghei. The inhibition of CHR on enzymatic activity of CYP1A2, CYP2A, CYP2C19, CYP2D6, CYP2E1, and CYP3A in rat liver microsome was also investigated. IC50, Km, Ki, and inhibitory type of CHR were respectively calculated. METHODS: Twenty rats were randomly divided into four groups and received three-day oral doses of ART in absence or presence of CHR (in ratio of 1:0, 1:1, 1:2, and 1:4, respectively). Plasma samples were separately harvested for ART pharmacokinetics analysis using a valid liquid chromatography tandem mass spectrometric (LC-MS/MS) method. Female Kunming mice were inoculated by P. berghei K173 strain and pre-exposed to three-day oral administration of ART with or without CHR as pharmacokinetics protocol. Giemsa staining method was applied to calculate percent parasitaemia (%) and inhibition (%). In vitro rat liver microsomal model was employed to elucidate the inhibitory effect of CHR on CYP1A2, CYP2A, CYP2C19, CYP2D6, CYP2E1, and CYP3A. RESULTS: The AUC0-t, Cmax, and t 1/2 of ART increased significantly (P < 0.05 or P < 0.01) as well as declined CLz (P < 0.05 or P < 0.01) after three-day oral doses of ART in presence of CHR (1:2) when compared with ART alone. Also, parasitaemia (%) remarkably attenuated 1.59 folds with 1.63-fold augmented inhibition (%) when the ratio between ART and CHR reached 1:2. CHR itself had no anti-malarial efficacy (P > 0.05). CHR inhibited in vitro activity of CYP1A2 and CYP2C19 (P < 0.01, IC50 = 4.61 and 6.23 µM) in a concentration-response manner. The inhibition did not emerge on CYP2E1 and CYP3A until the CHR concentration exceeded 4.0 µM (P < 0.01, IC50 = 28.17 and 3.38 µM). CHR has no impact on CYP 2A and CYP2D6 (P > 0.05). The inhibition types of CHR on CYP1A2 and CYP3A belonged to noncompetitive and uncompetitive, respectively. CONCLUSIONS: Co-administration of ART with CHR in ratio of 1:2 achieved a synergic anti-malarial effect partly because of the noncompetitive or uncompetitive inhibition of CHR of drug-metabolism enzymes, especially CYP3A which is closely related to the auto-induction of ART.
Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Sistema Enzimático do Citocromo P-450/análise , Inibidores Enzimáticos/farmacocinética , Flavonoides/farmacologia , Malária/tratamento farmacológico , Microssomos Hepáticos/enzimologia , Animais , Antimaláricos/farmacocinética , Artemisininas/farmacocinética , Cromatografia Líquida , Sinergismo Farmacológico , Feminino , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Plasma/química , Plasmodium berghei/efeitos dos fármacos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Resultado do TratamentoRESUMO
OBJECTIVES: To evaluate the influence of CYP2C19*2/*3 and MDR1 C3435T polymorphisms on the pharmacokinetics of lansoprazole (LPZ) in healthy Chinese subjects. METHODS: All 24 subjects were from a study of bioequivalence. Plasma concentrations of LPZ were determined by liquid chromatography/mass spectrometry. Cytochrome P450 (CYP) 2C19*2/*3 and multidrug resistance transporter gene 1 (MDR1) C3435T of the subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Significant differences were found in the area under the concentration-time curve from predose to T (AUC(0-T)), area under the concentration-time curve from predose to infinity (AUC(0-∞), t(1/2)), and apparent oral clearance (CL/F) of LPZ between CYP2C19 extensive metabolizers and intermediate metabolizers (p < 0.05). The AUC(0-T), AUC(0-∞), maximum plasma concentration, and CL/F of LPZ were significantly different between subjects with the MDR1 C3435T C/C, C/T, and T/T polymorphisms (p < 0.05). CONCLUSION: CYP2C19*2/*3 and MDR1 C3435T polymorphisms are important determinants of LPZ pharmacokinetics.
Assuntos
Citocromo P-450 CYP2C19/genética , Lansoprazol/farmacocinética , Polimorfismo Genético , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Área Sob a Curva , Genótipo , HumanosRESUMO
The paper reported an investigation of the pharmacokinetics of SN-38 (7-ethyl-10-hydroxy-camptothecin) in rats and the tissue distribution in mice after injection of irinotecan hydrochloride nanoparticles (CPT-11) via tail veins. An LC-MS/MS method was established to determine the concentrations of SN-38 in whole blood of rats and in different tissues of mice. The pharmacokinetics and tissue distribution of SN-38 were compared after the intravenous injection of CPT-11 NPs and CPT-11 solution. Compared with irinotecan solution, the elimination half-life of SN-38 was prolonged from 2.17 h to 2.67 h after the intravenous injection of CPT-11 NPs, but its AUC had little change. After the injection of CPT-11 NPs in mice, over time, the concentrations of CPT-11-metabolized SN-38 in CPT-11 NPs were significantly higher in the whole blood, colon and lungs than those in CPT-11 solution, followed by in the spleen and liver, but those in the heart and brain had no change. However, the amount of SN-38 in the kidneys was reduced with time. CPT-11 NPs could prolong SN-38's (one of its metabolites) blood circulation time in rats and significantly increased the concentration of CPT-11-metabolized SN-38 in the whole blood, colon and lungs of mice. CPT-11 NPs made SN-38 efficiently target-bind to the colon and lungs of mice.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Animais , Camptotecina/farmacocinética , Cromatografia Líquida , Colo/metabolismo , Meia-Vida , Injeções Intravenosas , Irinotecano , Pulmão/metabolismo , Camundongos , Nanopartículas/administração & dosagem , Ratos , Espectrometria de Massas em Tandem , Distribuição TecidualRESUMO
Multiple sclerosis (MS) is an autoimmune disease characterized by the infiltration of immune cells and demyelination in the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) serves as a prototypic animal model for studying MS. In this study, we aimed to investigate the role of CD4 T cells in the initiation and relapse of EAE, focusing on the activation phase and immune response. To create the EAE mice model, female mice were immunized with myelin oligodendrocyte glycoprotein (MOG)35-55 emulsified with complete Freund's adjuvant (CFA). Clinical scores were assessed daily, and results demonstrated that mice in the EAE group exhibited a classic relapsing-remitting pattern. Hematoxylin-eosin (H&E) and luxol fast blue (LFB) staining analysis revealed significant infiltration of inflammatory cells in the CNS and demyelination in EAE mice. Regarding the activation phase, both CD4+CD69+ effector T (Teff) cells and CD4+CD44+CD62L- effector memory T (Tem) cells may contribute to the initiation of EAE, however, the relapse stage was probably dominated by CD4+CD44+CD62L- Tem cells. Additionally, in terms of immune function, helper T (Th)1 cells are primarily involved in initiating the EAE. However, both Th1 and Th17 cells contribute to the relapse stage, and the immunosuppressive function of regulatory T (Treg) cells was inhibited during the EAE pathological process.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Feminino , Animais , Camundongos , Linfócitos T CD4-Positivos , Sistema Nervoso Central/patologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito , Recidiva , Camundongos Endogâmicos C57BLRESUMO
The object of this study is to investigate the pharmacokinetic interaction of pioglitazone hydrochloride and atorvastatin calcium in healthy adult Beagle dogs following single and multiple oral dose administration. A randomized, cross-over study was conducted with nine healthy adult Beagle dogs assigned to three groups. Each group was arranged to take atorvastatin calcium (A), pioglitazone hydrochloride (B), atorvastatin calcium and pioglitazone hydrochloride (C) orally in the first period, to take B, C, A in the second period, and to take C, A, B in the third period for 6 days respectively. The blood samples were collected at the first and the sixth day after the administration, plasma drug concentrations were determined by LC-MS/MS, a one-week wash-out period was needed between each period. The pharmacokinetic parameters of drug combination group and the drug alone group were calculated by statistical moment method, calculation of C(max) and AUC(0-t) was done by using 90% confidence interval method of the bioequivalence and bioavailability degree module DAS 3.2.1 software statistics. Compared with the separate administration, the main pharmacokinetic parameters (C(max) and AUC(0-t)) of joint use of pioglitazone hydrochloride and atorvastatin calcium within 90% confidence intervals for bioequivalence statistics were unqualified, the mean t(max) with standard deviation used paired Wilcoxon test resulted P > 0.05. There was no significant difference within t1/2, CL(int), MRT, V/F. Pioglitazone hydrochloride and atorvastatin calcium had pharmacokinetic interaction in healthy adult Beagle dogs.
Assuntos
Anticolesterolemiantes/farmacocinética , Atorvastatina/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hipoglicemiantes/farmacocinética , Tiazolidinedionas/farmacocinética , Administração Oral , Animais , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/sangue , Área Sob a Curva , Atorvastatina/administração & dosagem , Atorvastatina/sangue , Disponibilidade Biológica , Estudos Cross-Over , Cães , Interações Medicamentosas , Feminino , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Masculino , Pioglitazona , Distribuição Aleatória , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/sangueRESUMO
To investigate the pharmacokinetics of irinotecan hydrochloride (CPT-11) in rats and the tissue distribution of CPT-11 in mice after injection of irinotecan hydrochloride nanoparticles (CPT-11 NPs) via tail veins, separately, a LC-MS/MS method was established to determine the concentration of CPT-11 in whole blood of rats and in different tissues of mice. The pharmacokinetics and tissue distribution of CPT-11 were compared after the intravenous injection of CPT-11 NPs and CPT-11 solution. Compared with CPT-11 solution, the elimination half-life of CPT-11 was prolonged from 2.28 h to 3.95 h after the intravenous injection of CPT-11 NPs, and its AUC was 1.47 times than that of CPT-11 solution. After the injection of CPT-11 NPs in mice, the concentrations of CPT-11 loaded in CPT-11 NPs were significantly higher in the whole blood, colon and lungs than those in CPT-11 solution, but lower in the spleen, liver, kidney and heart, but the least in brain. CPT-11 NPs could improve CPT-11 's AUC, and help CPT-11 to reach long circulation activity.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Animais , Antineoplásicos Fitogênicos/sangue , Área Sob a Curva , Camptotecina/administração & dosagem , Camptotecina/sangue , Camptotecina/farmacocinética , Cromatografia Líquida de Alta Pressão , Feminino , Injeções Intravenosas , Irinotecano , Masculino , Camundongos , Nanopartículas , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Distribuição TecidualRESUMO
To analyze the sequence characteristics of mugwort pollen allergen Art v 1 protein and predict its B cell and Th (helper T cell) cell epitopes, the gene sequence and amino acid sequence of Art v 1 protein were obtained by referring to Genebank. ExPASy's Prot Param, TMHMM, DNAstar Protean, Swiss-Model, UCLA-DOE LAB SAVES v6.0, and IEDB were used to analyze and predict physicochemical properties, transmembrane region, secondary structure, tertiary structure, and B cell and Th cell epitopes of the protein. The Art v 1 protein is composed of 132 amino acid residues, the relative molecular weight is 13404.26, the molecular formula is C584H903N157O181S12, pI value is 7.49, the lipid solubility index is 41.59, and the hydrophilic index is -0.454, which is considered as hydrophilic protein. The instability index (ii) is 78.11, which is classified as an unstable protein. The N-terminus of the protein has an α-helical transmembrane region, which is located in the 5-27 amino acid residue sequence, and the 1-24 position is the signal peptide sequence. There are random coil, ß-turn, α-helix, and ß-sheet, and it also contains hydrophilic region, flexible region, and surface accessibility region structures. The prediction results of tertiary structure are consistent with the analysis results of secondary structure. Five dominant B cell epitopes were predicted, which were Art v 1 71-87, Art v 1 33-49, Art v 1 104-120, Art v 1 95-111, and Art v 1 86-102. There were five Th cell dominant epitopes, which were Art v 1 2-16, Art v 1 3-17, Art v 1 4-18, Art v 1 5-19, and Art v 1 6-20. The Art v 1 protein is predicted to have good antigenicity due to the presence of B cell and Th cell epitopes.
Assuntos
Artemisia , Epitopos de Linfócito B , Aminoácidos , Biologia Computacional , Alérgenos , PólenRESUMO
Theranostics is a new trend integrating diagnostic and therapeutic functions in tumour research. Theranostic nanoparticles enabling both tumour imaging and drug delivery are a promising platform for image-guided cancer therapy. Photodynamic therapy (PDT) has great potential in synergy with traditional chemotherapy but faces great challenges due to hypoxia, poor targeting ability and the limited penetration depth of visible light. To solve these problems, we presented a novel nanosystem of FA/UCNPs-RB/HCPT/PFH@lipid (denoted as FURH-PFH-NPs), with a perfluorohexane (PFH) carrying rich oxygen core and a folic acid-modified lipid shell. The shell contains 10-hydroxycamptothecin (HCPT) and self-fluorescing photosensitizer compounds, namely, upconversion nanoparticles and rose bengal (UCNPs-RB). In this study, FURH-PFH-NPs aggregated in SKOV3 cells (in vitro) and the nude xenograft tumour region when combined with folic acid receptors. When triggered by low-intensity focused ultrasound (LIFU), FURH-PFH-NPs released PFH, UCNPs-RB and HCPT. The above procedure was monitored through multimodal imaging, which simultaneously guided the tumour therapy. UCNPs-RB and PFH promoted the PDT effect under LIFU. Through PDT and HCPT, we obtained better therapeutic effects and good biosafety against SKOV3 nude xenograft tumours. FURH-PFH-NPs combined with LIFU and laser irradiation might be a promising strategy for ovarian cancer.
Assuntos
Corantes Fluorescentes/administração & dosagem , Fluorocarbonos/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Rosa Bengala/administração & dosagem , Nanomedicina Teranóstica , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Lasers , Luz , Camundongos Nus , Imagem Multimodal , Neoplasias/patologiaRESUMO
The influence of mPEG-PCL and mPEG-PLGA on encapsulation efficiency and drug-loading of nanoparticles was very important. SN-38 NPs were prepared from a series of diblock copolymers: mPEG1000-PLGA2000, mPEG2000-PCLs, mPEG5000-PCLs, mPEG2000-PLGAs, and mPEG5000-PLGAs by the thin film-hydration method. The prepared nanoparticles were characterized by morphology, size, encapsulation efficiency, drug-loading, and in vitro release behavior. This experiment suggested that the encapsulation efficiency and drug-loading of SN-38 NPs were attained the maximum values when the ratio of hydrophilic to hydrophobic block was between 1:2 and 1:3.
Assuntos
Camptotecina/análogos & derivados , Portadores de Fármacos , Nanopartículas/química , Poliésteres , Polietilenoglicóis , Camptotecina/química , Camptotecina/farmacocinética , Camptotecina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Irinotecano , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/farmacologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologiaRESUMO
Chronic myeloid leukemia (CML) treatment remains a challenge due to drug resistance and severe side effect, rendering the need on the development of novel therapeutics. CDDO-Me (Bardoxolone methyl), a potent Nrf2 activator and NF-κB inhibitor, is a promising candidate for cancer treatment including leukemia. However, the underlying mechanism for CDDO-Me in CML treatment is unclear. This study aimed to evaluate the molecular interactome of CDDO-Me in K562 cells using the quantitative proteomics approach stable-isotope labeling by amino acids in cell culture (SILAC) and explore the underlying mechanisms using cell-based functional assays. A total of 1,555 proteins responded to CDDO-Me exposure, including FANCI, SRPK2, XPO5, HP1BP3, NELFCD, Na+,K+-ATPase 1, etc. in K562 cells. A total of 246 signaling pathways and 25 networks regulating cell survival and death, cellular function and maintenance, energy production, protein synthesis, response to oxidative stress, and nucleic acid metabolism were involved. Our verification experiments confirmed that CDDO-Me down-regulated Na+,K+-ATPase α1 in K562 cells, and significantly arrested cells in G2/M and S phases, accompanied by remarkable alterations in the expression of key cell cycle regulators. CDDO-Me caused mitochondria-, death receptor-dependent and ER stress-mediated apoptosis in K562 cells, also induced autophagy with the suppression of PI3K/Akt/mTOR signaling pathway. p38 MAPK/Erk1/2 signaling pathways contributed to both apoptosis- and autophagy-inducing effects of CDDO-Me in K562 cells. Taken together, these data demonstrate that CDDO-Me is a potential anti-cancer agent that targets cell cycle, apoptosis, and autophagy in the treatment of CML.